Targeting NAD+ to Treat Chemotherapy and Radiotherapy Induced Cognitive Impairment, Neuropathies and Inactivity

ABSTRACT

Methods and compositions for preventing or treating peripheral neuropathy, cognitive deficits, inactivity, depression, chemotherapy and/or radiotherapy induced peripheral neuropathy and cognitive deficits, and improving cognitive performance, in a subject in need thereof are disclosed. The disclosed methods include the step of administering to the subject an effective amount of an agent that increases the level of NAD +  in the subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Patent Application Ser. No.62/153,876, filed Apr. 28, 2015, which is incorporated by referenceherein as if set forth in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

BACKGROUND

It is well-known that chemotherapy and radiotherapy can be neurotoxic,producing neural damage that can result in neuropathies and/or cognitiveimpairments. A significant subset of cancer survivors report ongoingcognitive problems after treatment, highlighting difficulties withmemory, working memory and attention [2]. The consequent impact on dailyfunction, return to work and quality of life has been described as themost troublesome survivorship issue that patients face [3]. Suchchemotherapy-induced cognitive impairments (CICI) have been verified inseveral ways. First, objective neuropsychological testing indicatesimpairment in processing speed, attention/concentration, executivefunction, and verbal and visual memory in 17-50% of survivors, whichpersist for years post-treatment [4]. Second, neuroimaging studies ofcancer survivors have correlated impaired performance in memory andexecutive function tasks with alterations in brain morphology andactivation patterns in areas important for these tasks, such as thehippocampus and pre-frontal cortices [5, 6], and with extensive whitematter abnormalities associated with cognitive impairment [7].

Further evidence shows that chemotherapy and radiotherapy haveneurotoxic side-effects. Many patients develop painful and disablingneuropathies during chemotherapy, especially those receiving taxanes,such as docetaxel, and platinum compounds, such as oxaliplatin.Estimates vary, with between 70-90% of patients experiencingchemotherapy-induced peripheral neuropathies (CIPN) during treatment[8]. CIPN can present as a progressive and enduring tingling numbness,intense pain and hypersensitivity to cold and touch, beginning in thehands and feet and sometimes involving the arms and legs. CIPN is asignificant source of distress during treatment, and can be therate-limiting factor in treatment leading to either dose reduction or,in rare cases, cessation of chemotherapy. These effects are lasting. At6 months after treatment, 30% of patients continue to experience CIPN[8] and are irreversible in 10-20% of patients [9]. CIPN has clearsevere negative effects on patients' quality of life, sleep and moodafter treatment [9].

Importantly, impairments in cognitive testing can occur in the absenceof changes in locomotor activity, or anxiety, anhedonia ordepressive-like behaviours [16]. Moreover, the cognitive impairmentspersist longer than allodynia in laboratory rats, indicating that poorperformance in cognitive testing is not related to disability associatedwith pain [11].

Chemotherapy can lead to inactivity, malaise and lethargy, which cancontribute to a downward spiral in health. Interventions that increasevoluntary activity could alleviate this, and improve physical,neurological and mental health of cancer survivors.

Chemotherapy can lead to depression, anxiety, circadian rhythm disordersincluding impaired sleep, mental health issues, neuropsychiatric andneuropsychological disorders, which can impair quality of life forcancer survivors.

NAD⁺ levels decline with age [17], and are raised by calorie restrictionand exercise in humans and in rodents. Interventions that raise NAD⁺(e.g., calorie restriction and exercise) have been shown to reducecancer risk and prevent tumor growth [19, 20], and reduce CIPN and CICI[42].

The NAD⁺ precursors nicotinamide mononucleotide (NMN) and nicotinamideriboside (NR) have been shown to improve metabolism and reverse aspectsof ageing in elderly mice [17].

Axon degeneration occurs frequently in neurodegenerative diseases andperipheral neuropathies. The degeneration of transected axons is delayedin Wallerian degeneration slow (Wlds) mice with the overexpression of afusion protein with the nicotinamide adenine dinucleotide (NAD⁺)synthetic enzyme, nicotinamide mononucleotide adenylyltransferase(Nmnat1). Both Wld(s) and Nmnat1 themselves are functional in preventingaxon degeneration in neuronal cultures.

NAD⁺ levels decrease in injured, diseased, or degenerating neural cells(Araki et al Science 2004).

In summary, anti-cancer treatment with chemotherapy and/or radiotherapyhas delivered increased survival rates for many cancers, at the cost ofsevere side effects that have a meaningful impact on survivor quality oflife, which in the case of CIPN and cognitive impairment impact thefeasibility of ongoing treatment. Thus, there is a need for newtherapeutic strategies to treat or prevent chemotherapy and/orradiotherapy induced cognitive impairment and/or neuropathies.

Neuronal injury or impairment can have a variety of causes.

Neuronal injury can cause cognitive deficits such as decreased memory,slower processing speed, decreased concentration/attention, impairedspatial, verbal and visual memory, impaired executive function, impairedsocial interactions, impaired verbal and non-verbal communication, andimpaired social interaction.

Neuronal injury can further cause mental health disorders such asdepression, anxiety, risk of self harm and suicide, substance addictionand abuse.

BRIEF SUMMARY

In one aspect, the present invention discloses a method for preventing,treating or providing increased resistance to neuropathy and/or pain;and associated disorders including cramps, neuromuscular paralysis, lossof sensation/numbness, tingling feeling, loss of motor skills, sexualdysfunction in a subject. The method comprises administering to thesubject an effective amount of an agent that increases the level of NAD⁺in the subject.

In another aspect, the present invention is a method for improvingcognitive function, including memory, processing speed, executivefunction, attention, concentration, and overall intelligence in asubject. The method comprises administering to the subject an effectiveamount of an agent that increases the level of NAD⁺ in the subject.

In another aspect, the present invention is a method for preventing ortreating cognitive deficits, neurocognitive deficits and/orneurodevelopmental disorders in a subject. The method comprisesadministering to the subject an effective amount of an agent thatincreases the level of NAD⁺ in the subject.

In another aspect, the present invention is a method for increasingvoluntary activity, increased endurance and stamina in a subject. Themethod comprises administering to the subject an effective amount of anagent that increases the level of NAD⁺ in the subject.

In another aspect, the present invention is a method for preventing ortreating inactivity, malaise, lethargy, and melancholy in a subject inneed thereof. The method comprises administering to the subject aneffective amount of an agent that increases the level of NAD⁺ in thesubject.

In another aspect, the present invention is a method for preventing ortreating depression, anxiety, post-traumatic stress disorder, and othermental health and psychological disorders in a subject. The methodcomprises administering to the subject an effective amount of an agentthat increases the level of NAD⁺ in the subject.

In another aspect, the present invention is a method for preventing ortreating sexual dysfunction associated with nerve damage and/orimpairment in a subject. The method comprises administering to thesubject an effective amount of an agent that increases the level of NAD⁺in the subject.

In another aspect, the present invention is a method for improvingneuronal function and motor skills in a subject. The method comprisesadministering to the subject an effective amount of an agent thatincreases the level of NAD⁺ in the subject.

In another aspect, the present invention is a method for preventing ortreating neurotoxic damage in a subject. The method comprisesadministering to a subject who has undergone psychological or physicalstress, exposure to toxic chemicals, radiation, shock, explosive shock,electrocution, mechanical injury, surgical injury, thermal injury,exhaustion, hypoxia, anoxia, blood loss, stroke, inflammation,auto-inflammation, infection, wound healing, malnutrition, drugaddiction, drug overdose, or other injuries, or will be exposed to saidstresses, an effective amount of an agent that increases the level ofNAD⁺ in the subject, whereby neurotoxic damage is prevented.

We disclose herein that raising NAD⁺ levels improves cognitiveperformance and prevents neurocognitive decline.

We disclose herein that raising NAD⁺ levels treats pain, and increasesresistance to pain.

We disclose herein that raising NAD⁺ levels increases voluntaryactivity, endurance and stamina.

In a first aspect, the disclosure encompasses a method for preventingtoxicity and damage to neural tissues during disease, psychologicalstress, physical stress, exposure to toxic chemicals, radiation, shock,explosive shock, electrocution, mechanical injury, surgical injury,thermal injury, exhaustion, hypoxia, anoxia, blood loss, stroke,malnutrition, drug addiction, drug overdose, wound healing,inflammation, infection, exposure to pollution such as air and waterpollution, or other injuries.

In some embodiments, the neurotoxic damage prevented is damage thatcauses neurocognitive impairment.

In some embodiments, the neurotoxic damage prevented is damage thatcauses pain and/or peripheral neuropathies.

In some embodiments, the neurotoxic damage prevented is damage thatcauses physical inactivity, lethargy or malaise.

In some embodiments, the neurotoxic damage prevented is damage thatcauses depression, anxiety, post-traumatic stress disorder, impairedsleep or other circadian rhythm disorders, impaired mental health orother neuropsychological disorders.

In another aspect, the disclosure encompasses a method for treatingpain, and providing resistance to increased pain.

We disclose herein that raising NAD⁺ levels provides robust protectionagainst chemotherapy-induced toxicity to healthy neural tissues, and canprevent or treat chemotherapy and/or radiotherapy-induced peripheralneuropathies (CIPN), chemotherapy and/or radiotherapy-induced cognitiveimpairments (CICI), and chemotherapy and/or radiotherapy inducedinactivity, lethargy, malaise, anxiety, depression, impaired sleep orother circadian rhythm disorders, impaired mental health or otherneuropsychological disorders.

In another aspect, the disclosure encompasses a method for preventingchemotherapy- and/or radiotherapy induced neurotoxic damage in asubject. The method includes the step of administering to a subject whohas undergone chemotherapy, is undergoing chemotherapy and/orradiotherapy, or will undergo chemotherapy and/or radiotherapy aneffective amount of an agent that increases the level of NAD⁺ in thesubject, whereby chemotherapy-induced neurotoxic damage is prevented.

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is damage that is associated withchemotherapy-induced cognitive impairments (CICI).

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is damage that is associated withchemotherapy and/or radiotherapy-induced peripheral neuropathies (CIPN).

In some embodiments, the chemotherapy and/or radiotherapy induced damageprevented is damage that is associated with chemotherapy and/orradiotherapy induced inactivity, lethargy or malaise.

In some embodiments, the chemotherapy and/or radiotherapy induced damageprevented is damage that is associated with chemotherapy and/orradiotherapy induced depression, anxiety, impaired sleep, circadianrhythm disorders, impaired mental health, or other neurophychological orneuropsychiatric disorders.

In some embodiments, the agent is administered before, at the same timeas, or after a chemotherapy agent is administered to the subject. Insome such embodiments, the chemotherapy agent is selected from a groupconsisting of cisplatin, carboplatin, oxaliplatin, cyclophosphamide,altretamine, plicamydin, chlorambucil, chlormethine, ifosfamide,melphalan, carmustine, fotemustine, lomustine, streptozocin, busulfan,dacarbazine, mechlorethamine, procarbazine, temozolomide, thioTEPA,uramustine, paclitaxel, docetaxel, vinblastine, vincristine, vindesine,vinorelbine, hexamethylmelamine, etoposide, teniposide, methotrexate,pemetrexed, raltitrexed, cladribine, clofarabine, fludarabine,mercaptopurine, tioguanine, capecitabine, cytarabine, fluorouracil,fluxuridine, gemcitabine, daunorubicin, doxorubicin, epirubicin,idarubicin, mitoxantrone, valrubicin, bleomycin, hydroxyurea, mitomycin,topotecan, irinotecan, aminolevulinic acid, methyl aminolevulinate,porfimer sodium, verteporfin, alitretinoin, altretamine, amsacrine,anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib,celecoxib, denileukin, diftitox, erlotinib, estramustine, gefitinib,hydroxycarbamide, imatinib, pentostatin, masoprocol, mitotane,pegaspargase, tretinoin, and combinations thereof.

In some embodiments, the agent is administered before, at the same timeas, or after radiotherapy.

In some embodiments, the agent that increases the level of NAD⁺ is anNAD⁺ precursor. In some such embodiments, the NAD⁺ precursor is selectedfrom the group consisting of nicotinamide mononucleotide (NMN),nicotinic acid, nicotinamide, nicotinamide riboside (NR), nicotinic acidmononucleotide, nicotinic acid riboside, AICAR, adenosine, adenine,adenosine monophosphate, an analog, hetero- or homo-dimer, oligomer orpolymer of any of the foregoing, or a salt or prodrug thereof.

In some embodiments, the agent that increases the level of NAD⁺ isadministered at a dose of between 0.5-5 grams per day.

In some embodiments, the agent that increases the level of NAD⁺ isselected from the group consisting of an enzyme involved in NAD⁺biosynthesis, an enzymatically active fragment of such an enzyme, anucleic acid encoding for an enzyme involved in NAD⁺ biosynthesis, andan enzymatically active fragment of such a nucleic acid. In some suchembodiments, the enzyme is NMNAT-1, NMNAT2, NMNAT3 or NAMPT.

In some embodiments, the agent that increases the level of NAD⁺ is anactivator to an enzyme involved in NAD⁺ biosynthesis.

In some embodiments, the agent that increases the level of NAD⁺ is aninhibitor of an NAD⁺ consuming enzyme such as CD38 or PARP. In oneembodiment, the agent may include apigenin, luteolin, tryphostin 8, aswell as some compounds developed by GSK: thiozoloquin(az)olin(on)es. SeeHaffner C D et al J Med Chem 2015.

In some embodiments, the subject is a human.

In another aspect, the disclosure encompasses an agent that increasesthe level of NAD⁺ for use in preventing chemotherapy and/orradiotherapy-induced neurotoxic damage in a subject.

In one aspect, the present invention is an agent that increases thelevel of NAD⁺ for use in preventing neurotoxic injury.

In another aspect, the present invention is an agent that increases thelevel of NAD⁺ for use in preventing neurocognitive and neuropathicdecline.

In another aspect, the present invention is an agent that increases thelevel of NAD⁺ for use in preventing or treating pain, neuropathies andassociated disorders; and providing increased resistance to pain,neuropathies and associated disorders.

In another aspect, the present invention is an agent that increases thelevel of NAD⁺ for use in increasing cognitive performance.

In another aspect, the present invention is an agent that increases thelevel of NAD⁺ for use in increasing voluntary activity, endurance, andstamina.

In another aspect, the present invention is an agent that increases thelevel of NAD⁺ for use in preventing cramps, tremors, spasms, paralysis,neuromuscular paralysis, hearing loss, vision impairment, taste loss,improving or preventing decline in skills, gait, and co-ordination.

In another aspect, the present invention is an agent that increases thelevel of NAD⁺ for use in preventing or treating sexual dysfunctionassociated with nerve damage or impairment.

In another aspect, the present invention is an agent that increases thelevel of NAD⁺ for use in improving neuronal function and motor skills.

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is damage that is associated withchemotherapy and/or radiotherapy-induced cognitive impairments (CICI).

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is damage that is associated withchemotherapy-induced peripheral neuropathies (CIPN).

In some embodiments, the chemotherapy and/or radiotherapy inducedneurotoxic damage prevented is damage that is associated withchemotherapy and/or radiotherapy-induced inactivity, lethargy ormalaise.

In some embodiments, the chemotherapy and/or radiotherapy inducedneurotoxic damage prevented is damage that is associated withchemotherapy and/or radiotherapy-induced depression, anxiety, impairedsleep, circadian rhythm disorder, or other psychological disorder.

In some embodiments, the agent is an NAD⁺ precursor. In some suchembodiments, the NAD⁺ precursor is selected from the group consisting ofnicotinamide mononucleotide (NMN), nicotinic acid, nicotinamide,nicotinamide riboside (NR), nicotinic acid mononucleotide, nicotinicacid riboside, AICAR, adenosine, adenine, adenosine monophosphate, ananalog, hetero- or homo-dimer, oligomer or polymer of any of theforegoing, or a salt or prodrug thereof.

In some embodiments, the agent that raises NAD⁺ is an inhibitor of anNAD+ consuming enzyme, such as CD38 or a PARP enzyme.

In some embodiments, the agent is selected from the group consisting ofan enzyme involved in NAD⁺ biosynthesis, an enzymatically activefragment of such an enzyme, a nucleic acid encoding for an enzymeinvolved in NAD⁺ biosynthesis, and an enzymatically active fragment ofsuch a nucleic acid. In some such embodiments, the enzyme is NMNAT-1,NMNAT2, NMNAT3 or NAMPT.

In some embodiments, the agent that increases the level of NAD⁺ is anactivator to an enzyme involved in NAD⁺ biosynthesis.

In some embodiments, the present invention is an agent that increasesthe level of NAD⁺ for use in manufacturing a medicament for preventingneural damage or decline.

In some embodiments, the present invention is an agent that increasesthe level of NAD⁺ for use in manufacturing a medicament for improvingneural function, including improved neurocognitive function.

In another aspect, the disclosure encompasses an agent that increasesthe level of NAD⁺ for use in manufacturing a medicament for preventingchemotherapy and/or radiotherapy-induced neurotoxic damage in a subject.

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is damage that is associated withchemotherapy and/or radiotherapy-induced cognitive impairments (CICI).

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is damage that is associated withchemotherapy-induced peripheral neuropathies (CIPN).

In some embodiments, the agent that increases the level of NAD⁺ is anNAD⁺ precursor. In some such embodiments, the NAD⁺ precursor is selectedfrom the group consisting of nicotinamide mononucleotide (NMN),nicotinic acid, nicotinamide, nicotinamide riboside (NR), nicotinic acidmononucleotide, nicotinic acid riboside, AICAR, adenosine, adenine,adenosine monophosphate, an analog, hetero- or homo-dimer, oligomer orpolymer of any of the foregoing, or a salt or prodrug thereof.

In some embodiments, the agent is selected from the group consisting ofan enzyme involved in NAD⁺ biosynthesis, an enzymatically activefragment of such an enzyme, a nucleic acid encoding for an enzymeinvolved in NAD⁺ biosynthesis, and an enzymatically active fragment ofsuch a nucleic acid. In some such embodiments, the enzyme is NMNAT-1,NMNAT2, NMNAT3 or NAMPT.

In some embodiments, the agent is an activator to an enzyme involved inNAD⁺ biosynthesis.

In another aspect, the present invention is a method for treatingneurotoxic damage, neuropathy or improving neural function in a subject.The method comprises administering to a subject in need thereof aneffective amount of an agent that increases the level of NAD⁺ in thesubject, whereby one of the symptoms of neurotoxic damage is decreased.

In one embodiment, the neurotoxic damage treated is damage that isassociated with cognitive impairment.

In one embodiment, the neurotoxic damage treated is damage that isassociated with peripheral neuropathy and/or pain.

In one embodiment, the neurotoxic damage treated is damage that isassociated with inactivity, lethargy and malaise.

In one embodiment, the neurotoxic damage treated is damage that isassociated with depression, anxiety, post-traumatic stress disorder,impaired sleep, circadian rhythm disruption, and otherneuropsychological disorders.

In another aspect, the disclosure encompasses a method for treatingchemotherapy and/or radiotherapy-induced neurotoxic damage in a subject.The method includes the step of administering to a subject in needthereof an effective amount of an agent that increases the level of NAD⁺in the subject, whereby one or more symptoms of chemotherapy-inducedneurotoxic damage is decreased.

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage treated is damage that is associated withchemotherapy-induced cognitive impairments (CICI).

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage treated is damage that is associated withchemotherapy-induced peripheral neuropathies (CIPN).

In some embodiments, the one or more symptoms of chemotherapy and/orradiotherapy-induced neurotoxic damage may include, without limitation,a burning sensation, a tingling sensation, loss of feeling, difficultyusing fingers to pick up or hold objects, dropping objects, difficultieswith balance, tripping or stumbling while walking, or pressure ortemperature sensitivity.

In one embodiment, the chemotherapy and/or radiotherapy-inducedneurotoxic treated is damage that is associated with inactivity,lethargy and malaise.

In one embodiment, the chemotherapy and/or radiotherapy-inducedneurotoxic treated is damage that is associated with depression,anxiety, impaired sleep, circadian rhythm disturbance, and other mentalhealth or neuropsychological disorders.

In some embodiments, the NAD⁺ raising agent is given in conjunction withexisting pain therapies, such as paracetamol, aspirin, ibuprofen,opioids, to improve efficacy, decrease the required dose ofco-administered pain therapies, or replace some agents in existing paintherapy combinations, or providing increased resistance to pain.

In some embodiments, the agent that increases the level of NAD⁺ is anNAD⁺ precursor. In some such embodiments, the NAD⁺ precursor is selectedfrom the group consisting of nicotinamide mononucleotide (NMN),nicotinic acid, nicotinamide, nicotinamide riboside (NR), nicotinic acidmononucleotide, nicotinic acid riboside, AICAR, adenosine, adenine,adenosine monophosphate, an analog, hetero- or homo-dimer, oligomer orpolymer of any of the foregoing, or a salt or prodrug thereof.

In some embodiments, the agent that increases the level of NAD⁺ is aninhibitor of an NAD⁺ consuming enzyme, such as CD38 or PARP.

In some embodiments, the agent that increases the level of NAD⁺ isadministered at a dose of between 0.5-5 grams per day. In someembodiments, the agent that increases the level of NAD⁺ is selected fromthe group consisting of an enzyme involved in NAD⁺ biosynthesis, anenzymatically active fragment of such an enzyme, a nucleic acid encodingfor an enzyme involved in NAD⁺ biosynthesis, and an enzymatically activefragment of such a nucleic acid. In some such embodiments, the enzyme isNMNAT-1, NMNAT2, NMNAT3 or NAMPT.

In some embodiments, the agent that increases the level of NAD⁺ is anactivator to an enzyme involved in NAD⁺ biosynthesis.

In one embodiment, the subject is a mammal selected from the groupconsisting of a racehorse, a companion pet and a livestock.

In some embodiments, the subject is a human.

In another aspect, the present invention is an agent that increases thelevel of NAD⁺ for use in treating neural damage in a subject.

In one embodiment, the neural damage treated or prevented is damage thatis associated with cognitive impairment.

In one embodiment, the neural damage treated or prevented is damage thatis associated with peripheral neuropathy and/or pain.

In one embodiment, the neural damage treated or prevented is damage thatis associated with inactivity, lethargy and malaise.

In one embodiment, the neural damage treated or prevented is damage thatis associated with depression, anxiety, impaired sleep, circadian rhythmdisturbances, impaired mental health, and other neuropsychologicaldisorders.

In one embodiment, the neural damage treated or prevented is damage thatis associated with psychological or emotional stress and associateddisorders, such as post-traumatic stress disorder.

In another aspect, the present invention is an agent that increases thelevel of NAD⁺ for use in preventing, treating pain and/or increasingresistance to pain.

In another aspect, the present invention is an agent that increases thelevel of NAD⁺ for use in improving neural function in a subject, toenhance cognitive performance, motor skills, voluntary activity, staminaand endurance, and provide resistance to pain and neuropathy.

In another aspect, the disclosure encompasses an agent that increasesthe level of NAD⁺ for use in treating chemotherapy and/orradiotherapy-induced neurotoxic damage in a subject.

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage treated is damage that is associated with chemotherapyand/or radiotherapy-induced cognitive impairments (CICI).

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is damage that is associated withchemotherapy and/or radiotherapy-induced peripheral neuropathies (CIPN).

In one embodiment, the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is inactivity, lethargy and malaise.

In one embodiment, the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is depression, anxiety, impaired sleep,impaired circadian rhythm, mental health disorders and otherneuropsychological disorders.

In some embodiments, the agent is an NAD⁺ precursor. In some suchembodiments, the NAD⁺ precursor is selected from the group consisting ofnicotinamide mononucleotide (NMN), nicotinic acid, nicotinamide,nicotinamide riboside (NR), nicotinic acid mononucleotide, nicotinicacid riboside, AICAR, adenosine, adenine, adenosine monophosphate, ananalog, hetero- or homo-dimer, oligomer or polymer of any of theforegoing, or a salt or prodrug thereof.

In some embodiments, the agent is selected from the group consisting ofan enzyme involved in NAD⁺ biosynthesis, an enzymatically activefragment of such an enzyme, a nucleic acid encoding for an enzymeinvolved in NAD⁺ biosynthesis, and an enzymatically active fragment ofsuch a nucleic acid. In some such embodiments, the enzyme is NMNAT-1,NMNAT2, NMNAT3 or NAMPT.

In some embodiments, the agent is an activator to an enzyme involved inNAD⁺ biosynthesis.

In another aspect, the disclosure encompasses an agent that increasesthe level of NAD⁺ for use in manufacturing a medicament for treatingchemotherapy and/or radiotherapy-induced neurotoxic damage in a subject.

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage treated is damage that is associated with chemotherapyand/or radiotherapy-induced cognitive impairments (CICI).

In some embodiments, the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is damage that is associated withchemotherapy and/or radiotherapy-induced peripheral neuropathies (CIPN).

In some embodiments, the agent is an NAD⁺ precursor. In some suchembodiments, the NAD⁺ precursor is selected from the group consisting ofnicotinamide mononucleotide (NMN), nicotinic acid, nicotinamide,nicotinamide riboside (NR), nicotinic acid mononucleotide, nicotinicacid riboside, AICAR, adenosine, adenine, adenosine monophosphate, ananalog, hetero- or homo-dimer, oligomer or polymer of any of theforegoing, or a salt or prodrug thereof.

In some embodiments, the agent is selected from the group consisting ofan enzyme involved in NAD⁺ biosynthesis, an enzymatically activefragment of such an enzyme, a nucleic acid encoding for an enzymeinvolved in NAD⁺ biosynthesis, and an enzymatically active fragment ofsuch a nucleic acid. In some such embodiments, the enzyme is NMNAT-1,NMNAT2, NMNAT3 or NAMPT.

In some embodiments, the agent is an activator to an enzyme involved inNAD⁺ biosynthesis.

In another embodiment, the agent is used to prevent, treat or increaseresistance to pain and neuropathies. Non-limiting examples of thisinclude chemical exposure, radiation exposure, light exposure, wounds,trauma, mechanical stress, thermal stress, high temperatures, lowtemperatures, sunburn, neuropathic diseases, or diseases that result indamage to nerves.

In another embodiment, the agent is administered in combination with orin place of painkillers, such as paracetamol, aspirin, ibuprofen, oropioids. Co-administration with the agent as disclosed here may be usedto lower the necessary dose of painkillers, and/or improve efficacy, orreplace the need for certain painkillers.

In another embodiment, the agent is used to treat neurological disordersthat result in memory loss or impaired cognitive functions, such asAlzheimer's disease, dementia, or Parkinson's disease.

In another aspect, the present invention is an agent that increases NAD⁺for improving pain tolerance.

In another aspect, the present invention is an agent that increases NAD⁺for treating phantom limbs.

In another aspect, the present invention is an agent that increases NAD⁺delivered prior to, at the same time as, in combination with, aftertreatment with, or in place of pain therapies such as ibuprofen,aspirin, paracetamol, opioids, and other pain therapies, for thetreatment of pain.

In another aspect, the present invention is an agent that increases NAD+delivered prior to, at the same time as, in combination with, aftertreatment with, or in place of anti-inflammatory therapies, includingwithout limitation corticosteroids selected from the group consisting ofdexamethasone and methylprednisolone and non-steroidal anti-inflammatoryagents selected from the group consisting of ibuprofen, aspirin,indomethacin, COX-2 inhibitors, and mefenamic acid for the treatment ofpain and neuropathies.

In another aspect, the present invention is an agent that increases NAD⁺for increasing voluntary physical activity, stamina and endurance.

In another aspect, the present invention is an agent that increases NAD⁺for improving cognitive performance.

In another aspect, the present invention is an agent that increases NAD⁺for treating or protecting against depression, anxiety, post-traumaticstress disorder, substance abuse, and other mental health orneuropsychological disorders.

In another aspect, the present invention is an agent that increases NAD⁺for preventing or treating diabetic neuropathy.

In another aspect, the present invention is an agent that increases NAD⁺for preventing or treating substance abuse and addiction.

In another aspect, the present invention is an agent that increases NAD⁺for preventing neurocognitive or neurodevelopmental disorders caused byexposure to pollution including air pollution, water pollution, and foodcontamination.

In another aspect, the present invention is an agent that prevents ortreats nerve and neuron damage.

In one embodiment, the NAD⁺ precursor is selected from the groupconsisting of nicotinamide mononucleotide (NMN), nicotinic acid,nicotinamide, nicotinamide riboside (NR), nicotinic acid mononucleotide,nicotinic acid riboside, AICAR, adenosine, adenine, adenosinemonophosphate, an analog, hetero- or homo-dimer, oligomer or polymer ofany of the foregoing, or a salt or prodrug thereof.

In one embodiment, the agent is selected from the group consisting of anenzyme involved in NAD⁺ biosynthesis, an enzymatically active fragmentof such an enzyme, a nucleic acid encoding for an enzyme involved inNAD⁺ biosynthesis, and an enzymatically active fragment of such anucleic acid.

In one embodiment, the enzyme is NMNAT-1, NMNAT2, NMNAT3 or NAMPT.

In one embodiment, the agent is an activator to an enzyme involved inNAD⁺ biosynthesis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D. Male SD rats were subjected to baseline testing prior toaddition of NMN to drinking water (500 mg/L) 24 prior and 24 hrsubsequent to a single i.p. injection of doxorubicin (4 mg/kg) with orwithout co-administration of NMN (200 mg/kg). A) Voluntary wheelrunning, followed by B) the von Frey test for mechanical allodynia(pain) at day 3. At day 8, C) short term spatial memory was assessedusing the novel location recognition test. At day 9, D) short termobject memory was assessed using the novel object recognition test. n=8,*p<0.05, **p<0.01, ****p<0.0001. Dunn's multiple comparison test,Kruskal Wallis one-way ANOVA.

FIGS. 2A-2B. A) His-tag western blot for expression of NMNAT3-Histransgene in brain. B) Palmitoyl-carnitine mitochondrial respiration intissue (liver) of NMNAT3 transgenics.

FIGS. 3A-3C. A) Experimental design for probing mitochondrialrespiration [43], B) example trace of 02 consumption rates in a Clarketype electrode, C) changes in respiratory capacity of musclemitochondria of aged NMN treated mice.

DETAILED DESCRIPTION I. Definitions

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The terms “optional” or “optionally” as used herein means that asubsequently described event or circumstance may but need not occur, andthat the description includes instances where the event or circumstanceoccurs and instances in which it does not. For example, “optional bond”means that the bond may or may not be present, and that the descriptionincludes single, double, or triple bonds.

The term “neuropathies” as used herein refers to any disease orcondition involving neurons and/or supporting cells, such as forexample, glia, muscle cells, fibroblasts, etc., and, in particular,those diseases or conditions involving axonal damage. Axonal damage canbe caused by traumatic injury, by non-mechanical injury due to diseasesor conditions, or by chemically induced injury or damage. The result ofsuch damage can be degeneration or dysfunction of the axon and loss offunctional neuronal activity. Disease and conditions producing orassociated with such axonal damage are among a large number ofneuropathic diseases and conditions. Such neuropathies can includeperipheral neuropathies, central neuropathies, and combinations thereof.Furthermore, peripheral neuropathic manifestations can be produced bydiseases focused primarily in the central nervous systems and centralnervous system manifestations can be produced by essentially peripheralor systemic diseases.

The term “chemotherapy-induced peripheral neuropathy” or “CIPN” as usedherein refers to a progressive, enduring, and often irreversiblecondition featuring pain, numbness, tingling and sensitivity to cold inthe hands and feet (sometimes progressing to the arms and legs), andesophagus, that afflicts between 30 and 40 percent of patientsundergoing chemotherapy. In CIPN, an anticancer drug could impair bothsensory and motor functions. The symptoms usually start in the handsand/or feet and creep up the arms and legs. Sometimes it feels like atingling or numbness. Other times, it's more of a shooting and/orburning pain or sensitivity to temperature. It can include sharp,stabbing pain. CIPN can also lead to hearing loss, blurred vision andchange in taste. CIPN can make it difficult to perform normal day-to-daytasks like buttoning a shirt, sorting coins in a purse, or walking. Inaddition, the motor neuron dysfunction manifest as cramps, difficultywith fine motor activities (e.g. writing or dialing a phone), gaitdisturbances, paralysis, spasms, tremors and weakness. Similardisturbances are observed during radiotherapy.

Chemotherapeutic agents are commonly grouped according to their mode ofaction and/or the cellular target upon which they act. For example,chemotherapeutic agents may categorized as DNA-interactive agents(including. topoisomerase inhibitors, DNA strand breakage agents and DNAminor groove binders), alkylating agents, antimetabolites,tubulin-interactive agents and hormonal agents. Chemotherapeutic agentsto which methods of the present application are applicable may beselected from any of these exemplary groups, but are not limitedthereto. For a detailed discussion of chemotherapeutic agents and theirmethod of administration, see Dorr, et al, Cancer Chemotherapy Handbook,2d edition, pages 15-34, Appleton and Lang (Connecticut, 1994) hereinincorporated by reference.

Chemotherapy drugs or agents associated with CIPN include, but notlimited to, arsenic trioxide (Trisenox), cytarabine (Cytosar-U, Depocyt,generics), etoposide, hexamethylmelamine (altretamine [Hexalen]),Ifosfamide (Ifex, generics), methotrexate (Trexall, generics),procarbazine (Matulane) and vinblastine, thalidomide, the epothilonessuch as Ixabepilone (Ixempra Kit), the vinca alkaloids vincristine andvinblastine, the taxanes paclitaxel and docetaxel, epothilones(ixabepilone), thalidomide (Thalomid), lenalidomide, the proteasomeinhibitors such as bortezomib (Velcade), and the platinum-based drugscisplatin, oxaliplatin and carboplatin.

By way of example only, according to methods of the invention,chemotherapeutic agents may be selected from cisplatin, carboplatin,oxaliplatin, cyclophosphamide, altretamine, plicamydin, chlorambucil,chlormethine, ifosfamide, melphalan, carmustine, fotemustine, lomustine,streptozocin, busulfan, dacarbazine, mechlorethamine, procarbazine,temozolomide, thioTEPA, uramustine, paclitaxel, docetaxel, vinblastine,vincristine, vindesine, vinorelbine, hexamethylmelamine, etoposide,teniposide, methotrexate, pemetrexed, raltitrexed, cladribine,clofarabine, fludarabine, mercaptopurine, tioguanine, capecitabine,cytarabine, fluorouracil, fluxuridine, gemcitabine, daunorubicin,doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin,bleomycin, hydroxyurea, mitomycin, topotecan, irinotecan, aminolevulinicacid, methyl aminolevulinate, porfimer sodium, verteporfin,alitretinoin, altretamine, amsacrine, anagrelide, arsenic trioxide,asparaginase, bexarotene, bortezomib, celecoxib, denileukin, diftitox,erlotinib, estramustine, gefitinib, hydroxycarbamide, imatinib,pentostatin, masoprocol, mitotane, pegaspargase, and tretinoin.

Whether CIPN arises, and to what degree, is determined by the choice ofdrug and/or radiotherapy, duration of use, the total amount consumed andwhether the patient already has peripheral neuropathy. Though thesymptoms are mainly sensory—pain, tingling, numbness, cramps,neuromuscular paralysis and temperature sensitivity—in some cases motornerves are affected, and occasionally, also, the autonomic nervoussystem.

CIPN often follows the first chemotherapy dose and increases in severityas treatment continues, but this progression usually levels off atcompletion of treatment. The platinum-based drugs are the exception;with these drugs, sensation may continue to deteriorate for severalmonths after the end of treatment and CIPN may persist for decadesfollowing treatment. Some CIPN appears to be irreversible. Pain canoften be helped with drug or other treatment but the numbness is usuallyresistant to treatment.

One of the mainstays of CIPN management is opioid based drug therapy.Opioid therapy presents clinical challenges such as opioid addiction,withdrawal symptoms, respiratory depression, constipation, dizziness,nausea, vomiting, constipation, and physical dependence. In addition,prescription of opioid therapies presents opportunities for abuse andcriminal activity. Alternatives to opioid based therapies would bepreferable from a medical perspective, psychological perspective andfrom a law enforcement perspective.

CIPN disrupts leisure, work and family relations, and the pain of CIPNis often accompanied by sleep and mood disturbance, fatigue andfunctional difficulties. A 2007 American study found that most patientsdid not recall being told to expect CIPN, and doctors monitoring thecondition rarely asked how it affects daily living but focused onpractical effects such as dexterity and gait. It is not known whatcauses the condition, but microtubule and mitochondrial damage, andleaky blood vessels near nerve cells are some of the possibilities beingexplored.

The terms “chemotherapy-induced cognitive dysfunction or impairment,”“CICI,” “post-chemotherapy cognitive impairment,” or “PCCI” as usedherein refer to the cognitive impairment that can result fromchemotherapy treatment. Approximately 20-30% of people who undergochemotherapy experience some level of post-chemotherapy cognitiveimpairment.

CICI may seriously affect quality of life and life itself in cancerpatients. CICI may manifest in many ways, including encephalopathysyndromes and confusional states, seizure activity, headache,cerebrovascular complications and stroke, visual loss, cerebellardysfunction, and spinal cord damage with myelopathy. It is now knownthat, as a result of treatment, a subset of cancer survivors experiencecognitive problems that can last for many years after the completion ofchemotherapy. The cognitive problems include attention deficits, memoryloss, and confused thought processes. Up to 70% of patients report thattheir cognitive difficulties persist well beyond the duration oftreatment.

The etiology of chemotherapy and/or radiotherapy-induced cognitiveimpairment is largely unknown, but several candidate mechanisms havebeen suggested, including oxidative stress, impaired blood-brain barrier(BBB), neuroinflammation, decreased neurogenesis, etc.

As used herein the terms “treating”, “treatment”, “preventing” and“prevention” refer to any and all uses which remedy a condition orsymptoms, prevent the establishment of a condition or disease, orotherwise prevent, hinder, retard, or reverse the progression of acondition or disease or other undesirable symptoms in any waywhatsoever. Thus the terms “treating” and “preventing” and the like areto be considered in their broadest context, For example, treatment doesnot necessarily imply that a patient is treated until total recovery.Similarly, in the present context, treatment also includes within itsscope the reversal of existing nerve damage or neuropathy, but notnecessarily the complete reversal thereof to normal levels that would beexpected in the absence of such nerve damage or neuropathy havingoccurred.

The term “neuropathy-associated condition” as used herein refers to acondition associated with, at least in part, nerve damage, in particularto neurons of the peripheral nervous system. The condition may becharacterized by such damage, may occur as a result, either directly orindirectly, of such damage or itself lead to such nerve damage.Typically a “neuropathy-associated condition” will share at least onesymptom in common with neuropathy, typically peripheral neuropathy, Suchsymptoms include pain, loss of sensation, including numbness, tinglingor burning sensations in limbs or body extremities, parasthesia, muscleweakness, a reduction in neuromuscular reflex, cramping, neuromuscularparalysis, and sexual dysfunction.

As used herein, the term “subject” means a human or non-human animalselected for treatment or therapy. The phrases“therapeutically-effective amount” and “effective amount” as used hereinmeans the amount of an agent which is effective for producing thedesired therapeutic effect in at least a sub-population of cells in asubject at a reasonable

As used herein, the term “prodrug” means a derivative of a compound thatcan hydrolyze, oxidize, or otherwise react under biological conditions(in vitro or in vivo) to provide a compound described herein as usefulin the methods of the invention. While prodrugs typically are designedto provide active compound upon reaction under biological conditions,prodrugs may have similar activity as a prodrug. The references byGoodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed,McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p 13-15); T.Higuchi and V. Stella (Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series); and Bioreversible Carriers in Drug Design(E. B. Roche, ed., American Pharmaceutical Association and PergamonPress, 1987) describing pro-drugs generally are hereby incorporated byreference. Prodrugs of the compounds described herein can be prepared bymodifying functional groups present in said component in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent component. Typical examples of prodrugs aredescribed for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO99/33792, each of which is incorporated herein by reference for theseteachings. Prodrugs can be characterized by increased bio-availabilityand are readily metabolized into the active inhibitors in vivo.

Examples of prodrugs include, but are not limited to, analogs orderivatives of the compounds described herein, further comprisingbiohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzableesters, biohydrolyzable carbamates, biohydrolyzable carbonates,biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Otherexamples of prodrugs include derivatives of the compounds describedherein that comprise NO, N02, ONO, or ON02 moieties. Prodrugs areprepared using methods known to those of skill in the art, such as thosedescribed by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995)172-178, 949-982 (Manfred E. Wolff ed., 5th ed), the entire teachings ofwhich are incorporated herein by reference.

As used herein, the term “salt” or “pharmaceutically acceptable salt”refers to those salts which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response andthe like, and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, Berge et al., describes pharmaceutically acceptable salts indetail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceuticallyacceptable salts of the compounds of this invention include thosederived from suitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N+(C1-4alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, andaryl sulfonate.

As used herein, the term “solvate” includes any combination which may beformed by a compound of this invention with a suitable inorganic solvent(e.g. hydrates) or organic solvent, such as but not limited to alcohols,ketones, esters and the like. Such salts, hydrates, solvates, etc. andthe preparation thereof will be clear to the skilled person; referenceis for instance made to the salts, hydrates, solvates, etc. described inU.S. Pat. No. 6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat. No.6,369,087 and U.S. Pat. No. 6,372,733.

As used herein, the term “NAD⁺ precursor” refers to a precursor compoundthat is capable of incorporated into NAD⁺ under physiological condition.Some exemplary NAD⁺ precursors include, without limitation, tryptophan,quinolinic acid, nicotinic acid, nicotinamide, nicotinamidemononucleotide (NMN) nicotinamide riboside (NR), nicotinic acidmononucleotide, nicotinic acid riboside, AICAR, adenosine, adenine,adenosine monophosphate, and analogues, hetero- or homo-dimers,oligomers, polymers and prodrugs thereof.

As used herein, the term “increase NAD⁺ level” refers to any means ormethod which can increase NAD⁺ level in a subject. For example, one mayincrease NAD⁺ level in a subject by administering to the subject aneffective amount of an agent that increases the level of NAD⁺ in thesubject. Examples of such agents include any NAD⁺ precursor as discussedabove and as appreciated by one skilled in the art, such as NMN or asalt thereof or prodrug thereof. Other examples of agents may include anenzyme involved in NAD⁺ biosynthesis, such as NMNAT-1 or NAMPT, or anenzymatically active fragment thereof, or a nucleic acid encoding anenzyme involved in NAD⁺ biosynthesis, or an enzymatically activefragment thereof.

NAD⁺ levels may be increased by increasing the activity of enzymesinvolved in NAD⁺ biosynthesis (de novo synthesis or salvage pathways).Enzymes involved in NAD⁺ biosynthesis such as nicotinate phosphoribosyltransferase 1 (NPT1), pyrazinamidase/nicotinamidase 1 (PNC1), nicotinicacid mononucleotide adenylyltransferase 1 (NMA1), nicotinic acidmononucleotide adenylyltransferase 2 (NMA2), nicotinamideN-methyltransferase (NNMT), nicotinamide phosphoribosyl transferase(NAMPT or NAMPRT), nicotinate/nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1), and nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2); are described in U.S. Pat. No. 7,977,049, whichis incorporated by reference herein.

In one embodiment, NAD⁺ levels in a subject may be increasedadministering to a subject an agent that increases the protein oractivity level of the enzymes involved in NAD⁺ biosynthesis as discussedabove.

In certain embodiments, agents for such uses include soluble precursorsto NAD⁺ (e.g., tryptophan, quinolinic acid, nicotinamide mononucleotide,nicotinamide riboside, and nicotinic acid), fisetin, quercetin,resveratrol, DOI, hydroxytyrosol, pyrroloquinoline quinone, metformin,apigenin, luteolin, tryphostin 8, berberine, a CD38 inhibitor, SRT-1720,a SIRT1 activator, a compound of any one of formulas I-XV, or functionalderivatives thereof.

The term “purified,” as described herein, refers to the purity of agiven compound. For example, a compound is “purified” when the givencompound is a major component of the composition, i.e., at least 50% w/wpure. Thus, “purified” embraces at least 50% w/w purity, at least 60%w/w purity, at least 70% purity, at least 80% purity, at least 85%purity, at least 90% purity, at least 92% purity, at least 94% purity,at least 96% purity, at least 97% purity, at least 98% purity, at least99% purity, at least 99.5% purity, and at least 99.9% purity, wherein“substantially pure” embraces at least 97% purity, at least 98% purity,at least 99% purity, at least 99.5% purity, and at least 99.9% purity.

The term “metabolite,” as described herein, refers to a compoundproduced in vivo after administration to a subject in need thereof.

The term “about” means that the recited numerical value is part of arange that varies within standard experimental error.

The term “salts,” as described herein, refers to a compound comprising acation and an anion, which can produced by the protonation of aproton-accepting moiety and/or deprotonation of a proton-donatingmoiety. It should be noted that protonation of the proton-acceptingmoiety results in the formation of a cationic species in which thecharge is balanced by the presence of a physiological anion, whereasdeprotonation of the proton-donating moiety results in the formation ofan anionic species in which the charge is balanced by the presence of aphysiological cation.

The phrase “pharmaceutically acceptable salt” means a salt that ispharmaceutically acceptable. Examples of pharmaceutically acceptablesalts include, but are not limited to: (1) acid addition salts, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as glycolic acid, pyruvic acid, lactic acid,malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid,citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid,gluconic acid, glutamic acid, salicylic acid, muconic acid, and the likeor (2) basic addition salts formed with the conjugate bases of any ofthe inorganic acids listed above, wherein the conjugate bases comprise acationic component selected from among Na⁺, K⁺, Mg²⁺, Ca²⁺,NH_(g)R′″⁴⁻g⁺, in which R′″ is a C₁₋₃ alkyl and g is a number selectedfrom among 0, 1, 2, 3, or 4. It should be understood that all referencesto pharmaceutically acceptable salts include solvent addition forms(solvates) or crystal forms (polymorphs) as defined herein, of the sameacid addition salt.

The term “preparation” or “dosage form” is intended to include bothsolid and liquid formulations of the active compound and one skilled inthe art will appreciate that an active ingredient can exist in differentpreparations depending on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is used toprepare a pharmaceutical composition, and is generally safe, non-toxicand neither biologically nor otherwise undesirable, and includesexcipients that are acceptable for veterinary use as well as humanpharmaceutical use.

“Nicotinamide,” which corresponds to the following structure,

is one of the two principal forms of the B-complex vitamin niacin. Theother principal form of niacin is nicotinic acid; nicotinamide, ratherthan nicotinic acid, however, is the major substrate for nicotinamideadenine dinucleotide (NAD) biosynthesis in mammals, as discussed indetail herein. Nicotinamide, in addition to being known as niacinamide,is also known as 3-pyridinecarboxamide, pyridine-3-carboxamide,nicotinic acid amide, vitamin B3, and vitamin PP. Nicotinamide has amolecular formula of C₆H₆N₂O and its molecular weight is 122.13 Daltons.Nicotinamide is commercially available from a variety of sources.

“Nicotinamide Adenine Dinucleotide” (NAD), which corresponds to thefollowing structure,

is produced from the conversion of nicotinamide to NMN, which iscatalyzed by Nampt, and the subsequent conversion of NMN to NAD, whichis catalyzed by Nmnat. Nicotinamide adenine dinucleotide (NAD) has amolecular formula of C₂₁H₂₇N₇O₁₄P₂ and a molecular weight of 663.43.Nicotinamide adenine dinucleotide (NAD) is commercially available fromsuch sources as Sigma-Aldrich (St. Louis, Mo.). Nicotinamide adeninedinucleotide exists in two forms, an oxidized and reduced formabbreviated as NAD⁺ and NADH respectively.

“Nicotinamide Mononucleotide” (NMN), which corresponds to the followingstructure,

is produced from nicotinamide in the NAD biosynthesis pathway, areaction that is catalyzed by Nampt. NMN is further converted to NAD inthe NAD biosynthesis pathway, a reaction that is catalyzed by Nmnat.Nicotinamide mononucleotide (NMN) has a molecular formula of C₁₁H₁₅N₂O₈Pand a molecular weight of 334.22. Nicotinamide mononucleotide (NMN) iscommercially available from such sources as Sigma-Aldrich (St. Louis,Mo.).

“Nicotinamide Riboside” (NR), which corresponds to the followingstructure,

is characterized and a synthesized as described in, for instance, U.S.Pat. No. 8,106,184.

“Nicotinic Acid Mononuceotide” (NaMN) corresponds to the followingstructure:

“Nicotinic Acid Riboside” (NaR) corresponds to the following structure:

“5-aminoimidazole-4-carboxamide ribonucleotide” (AICAR), whichcorresponds to the following structure,

is a precursor of adenine dinucleotide (AMP).

II. Increasing NAD⁺ Level Prevents Short and Long Term Chemotherapyand/or Radiotherapy Induced Peripheral Neuropathy and Cognitive DeficitsDuring Chemotherapy Administration

Chemotherapy and radiotherapy are crucial components of anticancertreatment and have led to dramatically increased survival rates in manycancers. While effective at killing cancer cells, a key, limiting factorin treatment is the fact that chemotherapeutic agents and radiotherapyhave widespread toxicity to healthy tissues throughout the body,including the brain and nervous system. In the short term, this leads topainful neuropathies, fatigue, and neuropsychological impairments, allof which commonly extend to years after treatment. Preventing andtreating neuropathies and neuropsychological impairments caused bychemotherapy and/or radiotherapy is therefore a critical goal inimproving the quality of life of cancer patients, and improving theirlong term health outcomes.

Chemotherapy and/or radiotherapy induced loss of NAD⁺ may lead toderanged gene expression, mitochondrial function, and reduced metaboliccapacity which may underlie the neuropsychological disorders andneuropathic pain that results from cancer chemotherapy. This decline inNAD+ and subsequent metabolic and epigenetic dysfunction can be rescuedby treatment with the cell permeable NAD+ precursor nicotinamidemononucleotide (NMN). Applicants' preliminary data shows that brief NMNtreatment rescues neurocognitive deficiencies caused by theanthracycline chemotherapeutic doxorubicin, including impaired memory,decreased voluntary activity, and mechanical allodynia.

In one aspect, the present invention is a method for preventing ortreating short and long term chemotherapy and/or radiotherapy inducedperipheral neuropathy and cognitive deficits during chemotherapyadministration by increasing NAD⁺ level in a subject. Applicants foundthat increasing NAD⁺ level in a subject can lead to preventing ortreating short and long term chemotherapy induced peripheral neuropathy.By way of an example, Applicants demonstrate that administering a NAD⁺precursor (i.e., NMN) to increase NAD⁺ level in a subject could lead topreventing or treating short and long term chemotherapy inducedperipheral neuropathy.

In one embodiment, the method for preventing or treating chemotherapyand/or radiotherapy induced peripheral neuropathy and cognitive deficitsin a subject in need thereof during chemotherapy and/or radiotherapyadministration comprising the step of administering to the subject aneffective amount of an agent that increases the level of NAD⁺ in thesubject.

In one embodiment, the agent is an NAD⁺ precursor. In one specificembodiment, the NAD⁺ precursor is NMN or a salt thereof, or a prodrugthereof. Example 1 and FIG. 1 showed that NAD+ precursor NMN iseffective in treating and preventing memory impairments, inactivity andallodynia caused by doxorubicin. As shown in FIG. 1, a single dose ofdoxorubicin caused neurocognitive defects including reduced voluntarywheel running, increased pain, and reduced short term spatial memory.Strikingly, administration of NMN reduced the effects of doxorubicin inall of these measurements, confirming that NMN treatment can at leastalleviate neurocognitive defects caused by chemotherapy and/orradiotherapy treatment.

The as-disclosed method may include the use of any other NAD⁺ precursorfor increasing NAD⁺ level. For example, one could administrate a subjectany other NAD⁺ precursor as appreciated by one skilled in the art toincrease NAD⁺ level in the subject. Some exemplary NAD⁺ precursors mayinclude tryptophan, quinolinic acid, nicotinic acid, nicotinamide,nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR).

In one embodiment, additional NAD⁺ precursors may form fromdimerization, oligomerization, and polymerization of another known NAD⁺precursor, e.g., NMN.

The as-disclosed method may also include the use of any other agents forincreasing NAD⁺ level. In one embodiment, an agent is an enzyme involvedin NAD⁺ biosynthesis, or an enzymatically active fragment thereof, or anucleic acid encoding an enzyme involved in NAD⁺ biosynthesis, or anenzymatically active fragment thereof. For example, one may increaseNAD⁺ level in a subject by administering an effective amount of anenzyme involved in NAD⁺ biosynthesis, or an enzymatically activefragment thereof, or a nucleic acid encoding an enzyme involved in NAD⁺biosynthesis, or an enzymatically active fragment thereof.

Enzymes involved in NAD⁺ biosynthesis may include nicotinatephosphoribosyl transferase 1 (NPT1), pyrazinamidase/nicotinamidase 1(PNC1), nicotinic acid mononucleotide adenylyltransferase 1 (NMA1),nicotinic acid mononucleotide adenylyltransferase 2 (NMA2), nicotinamideN-methyltransferase (NNMT), nicotinamide phosphoribosyl transferase(NAMPT or NAMPRT), nicotinate/nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1), nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) and nicotinamide mononucleotide adenylyltransferase 3 (NMNAT-3) as described in U.S. Pat. No. 7,977,049, whichis incorporated by reference herein.

NAD⁺ levels may be increased by increasing the activity of enzymesinvolved in NAD⁺ biosynthesis (de novo synthesis or salvage pathways).Thus, in one embodiment, the agent of the present invention may be anysubstance that is capable of increasing the activity of related enzymes.For example, the agent may be any of the activators that are known inthe art to activate the related enzymes.

Any means for increasing NAD⁺ level may be used to prevent or treatshort and long term chemotherapy and/or radiotherapy induced peripheralneuropathy and cognitive deficits during chemotherapy and/orradiotherapy administration.

In one embodiment, symptoms of chemotherapy and/or radiotherapy inducedperipheral neuropathy (CIPN) may include, but are not limited to,burning, tingling (“pins and needles” feeling), loss of feeling (can benumbness or just less ability to sense pressure, touch, heat, or cold),trouble using fingers to pick up or hold things, dropping things,balance problems, trouble with tripping or stumbling while walking,pressure or temperature hurt more than usual (mostly cold; this iscalled cold sensitivity), shrinking muscles, muscle weakness, troubleswallowing, constipation, trouble passing urine, blood pressure changes,altered nerve conduction velocity with decreased or no reflexes, cramps,neuromuscular paralysis, and sexual dysfunction. A number of thesesymptoms are also associated with calcium signaling dysregulation aswell.

In one embodiment, typical symptoms of such peripheral neuropathies mayinclude weakness, numbness, paresthesia (abnormal sensations such asburning, tickling, pricking or tingling), sexual dysfunction, and painin the arms, hands, legs and/or feet. The neuropathy may also beassociated with mitochondrial dysfunction. Such neuropathies can exhibitdecreased energy levels, i.e. decreased levels of NAD and ATP.

In one specific embodiment, symptoms of CIPN may include tactile & coldallodynia, mechanical and thermal hyperalgesia, short term or long timememory loss, difficulty in spatial cognition, difficulty in executivefunction, or working memory loss.

The use of chemotherapy and/or radiotherapy agents is well known by oneskilled in the art.

To prevent or treat CIPN and cognitive deficits in a subject duringchemotherapy and/or radiotherapy administration, the agent of thepresent invention may be administered to the subject simultaneously withthe administration of a chemotherapy agent or right after theadministration of a chemotherapy agent, or a period of time aftercompleting chemotherapy and/or radiotherapy.

In one embodiment, a therapeutically effective amount of the agent ofthe present invention may be co-administered with the chemotherapyagent.

In another embodiment, a therapeutically effective amount of the agentof the present invention may be administered right after theadministration of the chemotherapy agent. By the term “right after,” wemeans that the agent is administered to a subject when the subject isstill under chemotherapy treatment.

In another embodiment, a therapeutically effective amount of the agentof the present invention may be administered after chemotherapytreatment has ceased, to avoid the possibility that these agents willinterfere with chemotherapy efficacy, or increase tumor growth.

In another embodiment, a therapeutically effective amount of the agentof the present invention may be administered to cancer survivors withlong term, persistent neuropathic or cognitive problems.

In one embodiment, the present invention discloses a composition or aformulation comprising an agent which is capable of increasing the levelof NAD⁺ in the subject. Such a composition or a formulation additionallyincludes a pharmaceutically acceptable medium selected from among anexcipient, carrier, diluent, and equivalent medium; and a compound asdescribed herein or as appreciated by one skilled in the art.

In one embodiment, the present invention discloses a composition or aformulation for manufacturing a medicament for the treatment and/orprophylaxis of any of the diseases or health conditions disclosedherein. The composition or formulation includes a pharmaceuticallyacceptable medium selected from among an excipient, carrier, diluent,and equivalent medium; and a compound as described herein or asappreciated by one skilled in the art.

II. Increasing NAD⁺ Level Reverses Pre-Existing Chemotherapy and/orRadiotherapy Induced Neurocognitive Disorders

In one aspect, the present invention is a method for treating andreversing pre-existing CIPN and cognitive deficits by increasing NAD⁺level in a subject.

In addition to preventing or treating short and long term CIPN andcognitive deficits during chemotherapy and/or radiotherapyadministration, Applicants envision that increasing NAD⁺ level couldalso treat or reverse pre-existing CIPN and cognitive deficits in asubject.

In one embodiment, a method for treating or reversing pre-existing CIPNand cognitive deficits in a subject in need thereof comprises the stepof administering to the subject an effective amount of an agent thatincreases the level of NAD⁺ in the subject.

In one embodiment, the agent is any NAD⁺ precursor as discussed above oras appreciated by one skilled in the art.

In one specific embodiment, the NAD⁺ precursor is NMN or a salt thereof,or a prodrug thereof.

In one embodiment, the agent is an enzyme involved in NAD⁺ biosynthesis,or an enzymatically active fragment thereof, or a nucleic acid encodingan enzyme involved in NAD⁺ biosynthesis, or an enzymatically activefragment thereof. The enzyme may be any of the enzyme as discussed aboveor as appreciated by one skilled in the art.

In one specific embodiment, the enzyme is NMNAT-1, NMNAT2, NMNAT3 orNAMPT.

In one embodiment, the agent may also be an activator to an enzymeinvolved in NAD⁺ biosynthesis.

In one embodiment, the subject is a human.

To prevent or treat pre-existing CIPN and cognitive deficits in asubject, the agent of the present invention may be administered to thesubject after the administration of a chemotherapy agent orradiotherapy. Preferably, the agent of the present invention may beadministered after the chemotherapy treatment or radiotherapy.

In one embodiment, the present invention discloses a composition or aformulation comprising an agent which is capable of increasing the levelof NAD⁺ in the subject. Such a composition or a formulation includes apharmaceutically acceptable medium selected from among an excipient,carrier, diluent, and equivalent medium; and a compound as describedherein or as appreciated by one skilled in the art.

In one embodiment, the present invention discloses a composition or aformulation for manufacturing a medicament for the treatment and/orprophylaxis of any of the diseases or health conditions disclosedherein. The composition or formulation includes a pharmaceuticallyacceptable medium selected from among an excipient, carrier, diluent,and equivalent medium; and a compound as described herein or asappreciated by one skilled in the art.

III. Increasing NAD⁺ Treats Pain

In one embodiment, the present invention provides a method ofadministering a therapeutically effective amount of the agent of thepresent invention to treat or prevent acute or chronic pain includingneuropathic pain, either alone or in combination with existing paintreatments. Pain may be induced by factors including but not limited toexposure to certain pharmaceuticals (e.g. chemotherapy), radiation,chemical exposure, wounds, burns, sunburn, shock, explosive shock,electrocution, inflammation, infection, wound healing, high temperature,low temperature, mechanical stress, surgery, neuropathic diseases,malnutrition, drug addiction, drug overdose, or diseases that result inneuropathy and/or pain.

In another embodiment, the agent may be used to treat pain incombination with or in place of painkillers, such as paracetamol,aspirin, ibuprofen, or opioids. Co-administration with the agent asdisclosed here may be used to lower the necessary dose of painkillers,and/or improve efficacy, or replace the need for certain painkillers.

In another embodiment, the agent is used to provide resistance to pain.

IV. Increasing NAD⁺ Treats Cognitive Deficits and Improve NeurocognitiveFunction

In one embodiment, the present invention provides a method for enhancingmemory and improving cognitive function in healthy or challengedindividuals. Non-limiting examples of cognitive function includeprocessing speed, executive function, attention span and concentration,verbal memory, visual memory, and spatial memory.

In another embodiment, the present invention provides a method fortreating any disease related to cognitive deficits. Some exemplarydiseases are listed below. However, Applicants envision that the presentinvention is applicable to any cognitive deficit disease as appreciatedby one skilled in the art. Specifically, the present invention providesa method for treating impairments in cognitive function, non-limitingexamples of which include processing speed, executive function,attention span and concentration, verbal memory, visual memory andspatial memory.

In another embodiment, the present invention provides a method forpreventing and/or treating neurocognitive and/or neurodevelopmentaldisorders caused by exposure to pollution such as air pollution (e.g.,PM 2.5 and PM 10 particles), water pollution, and pollutioncontamination of food.

In another embodiment, the present invention provides a method forpreventing and/or treating neurocognitive deficits and mental healthdisorders caused by psychological stress, such as combat duty, policingand other environments which may cause post-traumatic stress disorder.

In another embodiment, the present invention provides a method forpreventing and/or treating substance abuse and/or addiction.

Essential tremor (ET) is the most common movement disorder. It is asyndrome characterized by a slowly progressive postural and/or kinetictremor, usually affecting both upper extremities.

Parkinson disease (PD) is a progressive neurodegenerative disorderassociated with a loss of dopaminergic nigrostriatal neurons.

Alzheimer disease (AD) is the most common form of dementia. It is aprogressive degenerative disease of the brain, strongly associated withadvanced age. Over time, people with the disease lose their ability tothink and reason clearly, judge situations, solve problems, concentrate,remember useful information, take care of themselves, and even speak. Anumber of neurodegenerative diseases such as Alzheimer's disease executetheir biological impact in the brain. In some embodiments, the discloseddimers, oligomers and polymers release free compounds that are capableof passing the blood-brain-barrier (BBB).

Huntington disease (HD) is an incurable, adult-onset, autosomal dominantinherited disorder associated with cell loss within a specific subset ofneurons in the basal ganglia and cortex.

Ataxia is defined as an inability to maintain normal posture andsmoothness of movement. Neurologic symptoms and signs such as seizuresand movement disorders (e.g., dystonia, chorea) may accompany ataxia.

Catatonia is a state of apparent unresponsiveness to external stimuli ina person who is apparently awake. Epilepsy is defined as a chroniccondition characterized by spontaneous, recurrent seizures; seizure isdefined as a clinical event associated with a transient,hypersynchronous neuronal discharge.

Neuroleptic malignant syndrome (NMS) refers to the combination ofhyperthermia, rigidity, and autonomic dysregulation that can occur as aserious complication of the use of antipsychotic drugs.

Chorea is an involuntary abnormal movement, characterized by abrupt,brief, nonrhythmic, nonrepetitive movement of any limb, often associatedwith nonpatterned facial grimaces. Chorea gravidarum (CG) is the termgiven to chorea occurring during pregnancy.

Cortical basal ganglionic degeneration (CBGD) clinical characteristicinclude progressive dementia, parkinsonism, and limb apraxia.Dysfunction of the central or peripheral nervous system pathways maycause autonomic dysfunction.

Dystonia is a syndrome of sustained muscle contractions, usuallyproducing twisting and repetitive movements or abnormal postures.Writer's cramp is a form of task-specific focal dystonia.

Mental retardation (MR) is a condition in which intellectual capacity islimited significantly. Developmental disability describes a conditionthat limits an individual's ability to perform activities and roles asexpected in a certain social environment. Frequently, MR anddevelopmental disabilities are present simultaneously as a consequenceof brain damage.

Neuroacanthocytosis is a progressive neurologic disease characterized bymovement disorders, personality changes, cognitive deterioration, axonalneuropathy, and seizures. Most patients have acanthocytosis onperipheral blood smear at some point during the course of the disease.

Pelizaeus-Merzbacher disease (PMD) and X-linked spastic paraplegia type2 (SPG2) are at opposite ends of a clinical spectrum of X-linkeddiseases caused by mutations of the same gene, the proteolipid protein 1(PLP1) gene, and resulting in defective central nervous system (CNS)myelination. Clinical signs usually include some combination ofnystagmus, stridor, spastic quadriparesis, hypotonia, cognitiveimpairment, ataxia, tremor, and diffuse leukoencephalopathy on MRIscans.

Progressive supranuclear palsy (PSP), also known asSteele-Richardson-Olszewski syndrome, is a neurodegenerative diseasethat affects cognition, eye movements, and posture.

Striatonigral degeneration (SND) is a neurodegenerative disease thatrepresents a manifestation of multiple system atrophy (MSA). The othermanifestations are Shy-Drager syndrome (eg, autonomic failurepredominates) and sporadic olivopontocerebellar degeneration (sOPCA,cerebellum predominates).

Ischemic stroke occurs due to a loss of blood supply to part of thebrain, initiating the ischemic cascade. Brain tissue ceases to functionif deprived of oxygen for more than 60 to 90 seconds and after a fewhours will suffer irreversible injury possibly leading to death of thetissue, i.e., infarction. Atherosclerosis may disrupt the blood supplyby narrowing the lumen of blood vessels leading to a reduction of bloodflow, by causing the formation of blood clots within the vessel, or byreleasing showers of small emboli through the disintegration ofatherosclerotic plaques. Embolic infarction occurs when emboli formedelsewhere in the circulatory system, typically in the heart as aconsequence of atrial fibrillation, or in the carotid arteries. Thesebreak off, enter the cerebral circulation, then lodge in and occludebrain blood vessels.

Due to collateral circulation, within the region of brain tissueaffected by ischemia there is a spectrum of severity. Thus, part of thetissue may immediately die while other parts may only be injured andcould potentially recover. The ischemia area where tissue might recoveris referred to as the ischemic penumbra.

As oxygen or glucose becomes depleted in ischemic brain tissue, theproduction of high energy phosphate compounds such as adeninetriphosphate (ATP) fails leading to failure of energy dependentprocesses necessary for tissue cell survival. This sets off a series ofinterrelated events that result in cellular injury and death. Theseinclude the failure of mitochondria, which can lead further towardenergy depletion and may trigger cell death due to apoptosis. Otherprocesses include the loss of membrane ion pump function leading toelectrolyte imbalances in brain cells. There is also the release ofexcitatory neurotransmitters, which have toxic effects in excessiveconcentrations.

Spinal cord injury, or myelopathy, is a disturbance of the spinal cordthat results in loss of sensation and mobility. The two common types ofspinal cord injury are: Trauma: automobile accidents, falls, gunshots,diving accidents, etc. Disease: polio, spinabifida, tumors, Friedreich'sataxia, etc. It is important to note that the spinal cord does not haveto be completely severed for there to be a loss of function. In fact,the spinal cord remains intact in most cases of spinal cord injury.

Traumatic brain injury (TBI), traumatic injuries to the brain, alsocalled intracranial injury, or simply head injury, occurs when a suddentrauma causes brain damage. TBI can result from a closed head injury ora penetrating head injury and is one of two subsets of acquired braininjury (ABI). The other subset is non-traumatic brain injury (i.e.stroke, meningitis, anoxia). Parts of the brain that can be damagedinclude the cerebral hemispheres, cerebellum, and brain stem. Symptomsof a TBI can be mild, moderate, or severe, depending on the extent ofthe damage to the brain. Outcome can be anything from complete recoveryto permanent disability or death. A coma can also affect a child'sbrain. The damage from TBI can be focal, confined to one area of thebrain, or diffuse, involving more than one area of the brain. Diffusetrauma to the brain is frequently associated with concussion (a shakingof the brain in response to sudden motion of the head), diffuse axonalinjury, or coma. Localized injuries may be associated withneurobehavioral manifestations, hemiparesis or other focal neurologicdeficits.

Another insult to the brain that can cause injury is anoxia. Anoxia is acondition in which there is an absence of oxygen supply to an organ'stissues, even if there is adequate blood flow to the tissue. Hypoxiarefers to a decrease in oxygen supply rather than a complete absence ofoxygen, and ischemia is inadequate blood supply, as is seen in cases inwhich the brain swells. In any of these cases, without adequate oxygen,a biochemical cascade called the ischemic cascade is unleashed, and thecells of the brain can die within several minutes. This type of injuryis often seen in near-drowning victims, in heart attack patients(particularly those who have suffered a cardiac arrest, or in people whosuffer significant blood loss from other injuries that then causes adecrease in blood flow to the brain due to circulatory (hypovolemic)shock. Related conditions, such as would occur with severe wound healingor bleed out (e.g., Ebola cytokine storm suppression) can also betreated with the disclosed agents.

Post-chemotherapy cognitive impairment is characterized by temporary orlong-lasting neurocognitive deficits, including memory loss, decreasedprocessing speed, loss of executive function, and overall reductions inIQ. These problems are broadly applicable to patients receivingchemotherapy, and are of particular problems to patients who have or arereceiving chemotherapy during developmentally important phases (e.g.,childhood).

V. Increasing NAD⁺ to Improve Voluntary Activity, Lethargy, Malaise andMental Health Disorders

In one embodiment, the disclosed agents may be used to increasevoluntary physical activity in a healthy individual.

The disclosed agents may be used to increase physical stamina andendurance in a human or animal under healthy, disease challenged orinjured state.

The disclosed agents may be used to treat depression or depression likesymptoms.

In another embodiment, the disclosed agents may be used to prevent ortreat inactivity, lethargy and malaise in an affected individual in needthereof. Non-limiting examples include patients suffering nausea,illness, injury, post-traumatic stress disorder, or mental healthdisorders.

The disclosed agents may be used to prevent or treat depression ordepression like symptoms, including increased risk of self-harm.

The disclosed agents may be used to prevent or treat addictivebehaviours such as substance abuse.

The disclosed agents may be used to prevent or treat impaired socialdevelopment, including verbal and non-verbal communication.

In another example, the disclosed agents may be used to treatpsychological and mental health disorders such as depression, anxiety,post-traumatic stress disorders, impaired sleep, circadian rhythmdisorders.

In another embodiment, the disclosed agents may be used to treatchemotherapy induced inactivity, lethargy, malaise, and depression.

VI. Pharmaceutical Formulations and Routes of Administration

Pharmaceutical Formulations.

The disclosed agents may be formulated with conventional carriers andexcipients, which will be selected in accord with ordinary practice.Tablets may contain excipients, glidants, fillers, binders and the like.Aqueous formulations are prepared in sterile form, and when intended fordelivery by other than oral administration generally will be isotonic.All formulations will optionally contain excipients such as those setforth in the “Handbook of Pharmaceutical Excipients” (1986). Possibleexcipients include ascorbic acid and other antioxidants, chelatingagents such as EDTA, carbohydrates such as dextran,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations optionally ranges from about 3 to about11, but is ordinarily about 7 to 10.

The disclosed agents may be formulated with slow release carriers, suchas cellulose, ethyl cellulose, hydroxypropyl cellulose, dextran,hyaluronic acid and the like.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, comprise at leastone active ingredient, as above defined, together with one or moreacceptable carriers therefor and optionally other therapeuticingredients. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation andphysiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the disclosed agents suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween™ 60, Span™ 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations of the disclosed agents may comprise acombination of one or more such compounds together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets may be uncoated or may be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally-occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, a suspending agent, andone or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those disclosed above. Additionalexcipients, for example sweetening, flavoring and coloring agents, mayalso be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally-occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to10%, and particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns, such as0.5, 1, 30, 35 etc., which is administered by rapid inhalation throughthe nasal passage or by inhalation through the mouth so as to reach thealveolar sacs. Suitable formulations include aqueous or oily solutionsof the active ingredient. Formulations suitable for aerosol or drypowder administration may be prepared according to conventional methodsand may be delivered with other therapeutic agents such as compoundsheretofore used in the treatment or prophylaxis of HCV infections asdescribed below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

The disclosure further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

The disclosed agents are used to provide controlled releasepharmaceutical formulations containing as active ingredient one or morecompounds of the invention (“controlled release formulations”) in whichthe release of the active ingredient are controlled and regulated toallow less frequency dosing or to improve the pharmacokinetic ortoxicity profile of a given active ingredient. In a non-limitingexample, the size of the disclosed oligomers and polymers, which can beinversely correlated with rate of release of the therapeutic monomer,may be selected using size exclusion chromatography, filtration thoughmembranes, centrifugation or other methods.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses) or against an active viralinfection, the method of delivery, and the pharmaceutical formulation,and will be determined by the clinician using conventional doseescalation studies. It can be expected to be from about 0.0001 to about100 mg/kg body weight per day; typically, from about 0.01 to about 10mg/kg body weight per day; more typically, from about 0.01 to about 5mg/kg body weight per day; most typically, from about 0.05 to about 0.5mg/kg body weight per day. For example, the daily candidate dose for anadult human of approximately 70 kg body weight will range from 1 mg to1000 mg, preferably between 5 mg and 500 mg, and may take the form ofsingle or multiple doses.

Routes of Administration.

One or more of the disclosed agents (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

In another embodiment, one of the more disclosed agents is administeredduring surgery, through topical application to desired areas,intrathecal administration, bathing of tissues in the disclosed agents,or surgical placement of a slow release device, gel, or matrix.

VII. Description of Selected Exemplary Embodiments (Examples)

The following examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart from the foregoing description and the following examples and fallwithin the scope of the appended claims.

Example 1 NAD⁺ Precursor NMN is Effective in Treating and PreventingMemory Impairments, Inactivity and Allodynia Caused by Doxorubicin

In this Example, the strategy is to raise NAD⁺ levels duringchemotherapy treatment by administering animals with a cell permeableNAD⁺ precursor known as nicotinamide mononucleotide (NMN). NMN is abenign compound, found inside every cell in the body, and is convertedin one step to NAD⁺ by NMNAT enzymes (NMNAT1-3) localized to thenucleus, cytoplasm/golgi and mitochondria, respectively. Given previousinvestigations of chemotherapy induced memory loss [11-15, 37, 38], itwas determined whether NMN could ameliorate neurocognitive deficitscaused by doxorubicin, a commonly used anthracycline chemotherapeutic.As expected, a single dose of doxorubicin caused neurocognitive defectsincluding reduced voluntary wheel running, increased pain, and reducedshort term spatial memory (FIG. 1). Strikingly, administration of NMNreduced the effects of doxorubicin in all of these measurements,providing evidence for our hypothesis that NMN treatment can alleviateneurocognitive defects caused by chemotherapy treatment.

FIG. 1 demonstrates that Male Sprague-Dawley rats were subjected tobaseline testing prior to addition of NMN to drinking water (500 mg/L)24 prior and 24 hr subsequent to a single i.p. injection of doxorubicin(4 mg/kg) with or without co-administration of NMN (200 mg/kg).

The above data suggest that the NAD⁺ precursor NMN is effective intreating and preventing memory impairments, inactivity and allodyniacaused by doxorubicin.

In a prophetic extension, the NAD+ precursor will also improve otherparameters of memory, such as spatial cognition and long term memory, asassessed by a Morris water maze; executive function, as measured by amorris water maze test of reversal learning; and working memory, asassessed by a morris water maze matching to place test.

In addition to mechanical allodynia, in another prophetic extension, NMNwill also provide protection against tactile and thermal allodynia.

In prophetic extension, NMN will provide protection against otherchemotherapeutics, such as oxaliplatin or docetaxel.

Example 2 Extension of the Results of Example 1

In this prophetic example, we outline how to extend the aboveexperimental results in four ways. First, we propose that NMNadministration post-chemotherapy will be effective in reversing existingneuropathologies associated with CIPN and CICI. Secondly, we proposethat mice overexpressing the NAD⁺ biosynthetic enzymes NMNAT1 and NMNAT3will be protected against neuropathologies associated with CIPN andCICI. Third, we propose that histological and molecularcharacterisations of brain and nerve tissues will show that NMNtreatment, or NMNAT1 or NMNAT3 over-expression will demonstrateprotection against chemotherapy induced cellular apoptosis, necrosis,senescence, inflammation, impaired mitochondrial function, metabolicdysfunction, DNA damage, and other markers of neural damage.

In the above examples, treatment of animals with NAD⁺ treating compoundswill show increased voluntary activity, as measured by a running wheel,laser beam breaks of a metabolic cage, and video monitoring.

Example 3 Testing the Ability of NMN to Increase Physical Activity,Motor Co-Ordination, Stamina and Endurance

In this prophetic example, treatment of otherwise healthy animals withan NAD+ raising agent will increase distance run on a treadmill,performance on accelerating rotarod, and voluntary activity.

Example 4 Testing the Ability of NMN to Prevent or Treat Surgical NerveDamage

In this prophetic example, treatment of otherwise healthy animals withan NAD+ raising agent will increase distance run on a treadmill,performance on accelerating rotarod, and voluntary activity.

Example 5 Investigating the Molecular Response to Chemotherapy in theBrain During NMN Treatment, NMNAT1 and NMNAT3 Over-Expression

In this prophetic example, we propose performing a detailedcharacterization of the molecular pathways through which NMN protectsagainst CIPN and CICI. We will repeat doxorubicin with NMN treatment orin NMNAT1 and NMNAT3 transgenic mice as in Examples 3 and 5, and cullanimals one week post doxorubicin to obtain tissues for the molecularanalyses described below. For NMN treatment as listed in HypotheticalExample 3, we will use a strain of transgenic reporter mice, which allownon-invasive imaging of cellular senescence caused by toxins such aschemotherapy. We will in addition repeat doxorubicin treatment in NMNAT1and NMNAT3 transgenic mice and their WT littermates as described inExample 5.

Mitochondrial function will be assessed in freshly isolated brainmitochondria, and activity of each complex of the electrode transportchain will be assessed in a dissolved oxygen Clarke-type electrode aspreviously described [43] and as shown in FIG. 3. Substrates andinhibitors that are specific for each complex of the electron transportchain will be added, allowing calculation of activity of each complex.These data will be important in pinpointing the nature of anymitochondrial dysfunction, which we expect NMN or NMNAT3 over-expressionto reverse as we have found in preliminary data (FIGS. 2B and 3C) andrecently published [17].

Apoptosis will be measured through western blotting for cleaved caspase3 and γH2AX. DNA damage and PARP activity will be assessed by westernblotting for poly-ADP ribose (PAR). Immunohistochemical analysis ofapoptosis will be assessed as described below.

Gene expression will be profiled in the hippocampus using RNA sequencingto detect coding and non-coding RNA.

Histochemistry:

In some experiments, mice will be perfused with 4% paraformaldehydeunder anaesthesia, and the brains removed, post-fixed and sectioned. Thetissue will be prepared for histological analysis for pathologiesassociated with CIPN and CICI. Tissues to be examined will includespinal cord, brain, peripheral nerves, dorsal root ganglia. Tissues willbe stained for Ki67 as a marker for neurogenesis, TUNEL as a marker forDNA damage and apoptosis, and GFAP for glial cell activation.

Power Calculations:

The primary outcome for these studies will be complex IV respiratorycapacity of brain mitochondria. Assuming an effect size f=0.3, we willneed 126 animals per experiment. We will require separate animals fortranscardial perfusion of paraformaldehyde for subsequent histologicalanalysis, and will require an additional 94 animals (f=0.35). With NMNtreatment, NMNAT1 and NMNAT3 overexpression, we will require 660 mice intotal for this aim.

We expect that NMN will protect against chemotherapy induced loss ofNAD⁺, impaired mitochondrial function, neuronal toxicity, cellularsenescence, and apoptosis.

Other embodiments and uses will be apparent to those skilled in the artfrom consideration from the specification and practice of the inventiondisclosed herein. It is understood that the invention is not confined tothe specific reagents, formulations, reaction conditions, etc., hereinillustrated and described, but embraces such modified forms thereof ascome within the scope of the following claims.

Example 6 Surgical Damage to Neurons

In this prophetic example, mice will be subjected to nerve damagethrough surgical manipulation.

Before surgical manipulation, mice will be delivered NMN and/or AICARthrough i.p. injection, oral gavage or addition to drinking water.

Pain will be assessed post-surgery though various allodynia tests, andit is expected that NMN and/or AICAR pretreatment will prevent nervedamage resulting in pain or neuropathy.

In another prophetic example, NMN is applied to nerves during surgery,and allodynia is assessed afterwards. It is expected that application orimplantation of an NMN releasing device during surgery will reduce orprevent nerve damage resulting in pain or neuropathy.

All references cited herein for any reason, including all journalcitations and U.S./foreign patents and patent applications, arespecifically and entirely incorporated by reference herein.

REFERENCES

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1. A method for preventing, treating or providing increased resistanceto neuropathy and/or pain; and associated disorders including cramps,neuromuscular paralysis, loss of sensation/numbness, tingling feeling,loss of motor skills, sexual dysfunction in a subject, comprisingadministering to the subject an effective amount of an agent thatincreases the level of NAD⁺ in the subject.
 2. A method for improvingcognitive function, including memory, processing speed, executivefunction, attention, concentration, and overall intelligence in asubject, comprising administering to the subject an effective amount ofan agent that increases the level of NAD⁺ in the subject.
 3. A methodfor preventing or treating cognitive deficits, neurocognitive deficits,or neurodevelopmental disorders in a subject, comprising administeringto the subject an effective amount of an agent that increases the levelof NAD⁺ in the subject.
 4. A method for increasing voluntary activity,increased endurance and stamina in a subject, comprising administeringto the subject an effective amount of an agent that increases the levelof NAD⁺ in the subject.
 5. A method for preventing or treatinginactivity, malaise, lethargy, and melancholy in a subject in needthereof, comprising administering to the subject an effective amount ofan agent that increases the level of NAD⁺ in the subject.
 6. A methodfor preventing or treating depression, anxiety, post-traumatic stressdisorder, and other mental health and psychological disorders in asubject, comprising administering to the subject an effective amount ofan agent that increases the level of NAD⁺ in the subject.
 7. A methodfor preventing or treating sexual dysfunction associated with nervedamage and/or impairment in a subject, comprising administering to thesubject an effective amount of an agent that increases the level of NAD⁺in the subject.
 8. A method for improving neuronal function and motorskills in a subject, comprising administering to the subject aneffective amount of an agent that increases the level of NAD⁺ in thesubject.
 9. A method for preventing or treating neurotoxic damage in asubject, comprising administering to a subject who has undergonepsychological or physical stress, exposure to toxic chemicals,radiation, shock, explosive shock, electrocution, mechanical injury,surgical injury, thermal injury, exhaustion, hypoxia, anoxia, bloodloss, stroke, inflammation, auto-inflammation, infection, wound healing,malnutrition, drug addiction, drug overdose, or other injuries, or willbe exposed to said stresses, an effective amount of an agent thatincreases the level of NAD⁺ in the subject, whereby neurotoxic damage isprevented.
 10. A method for preventing chemotherapy and/orradiotherapy-induced neurotoxic damage in a subject, comprisingadministering to a subject who has undergone chemotherapy and/orradiotherapy, is undergoing chemotherapy and/or radiotherapy, or willundergo chemotherapy and/or radiotherapy an effective amount of an agentthat increases the level of NAD⁺ in the subject, whereby chemotherapyand/or radiotherapy-induced neurotoxic damage is prevented.
 11. Themethod of claim 10, wherein the chemotherapy- and/or radiotherapyinduced neurotoxic damage prevented is damage that is associated withchemotherapy and/or radiotherapy-induced cognitive impairments (CICI).12. The method of claim 10, wherein the chemotherapy and/orradiotherapy-induced neurotoxic damage prevented is damage that isassociated with chemotherapy and/or radiotherapy-induced peripheralneuropathies (CIPN).
 13. The method of claim 10, wherein thechemotherapy and/or radiotherapy induced neurotoxic damage prevented isdamage that is associated with chemotherapy and/or radiotherapy-inducedinactivity.
 14. The method of claim 10, wherein the chemotherapy and/orradiotherapy induced neurotoxic damage prevented is damage that isassociated with chemotherapy and/or radiotherapy-induced depression,anxiety, melancholy, post-traumatic stress disorder, impaired sleep,circadian rhythm disorders, or other mental health/psychologicaldisorder.
 15. The method of any of claims 8-14, wherein the agent isadministered before, at the same time as, or after a chemotherapy and/orradiotherapy agent is administered to the subject.
 16. The method ofclaim 9, wherein the neurotoxic damage prevented is damage that isassociated with cognitive impairments.
 17. The method of claim 9,wherein the neurotoxic damage prevented is damage that is associatedwith pain and/or peripheral neuropathies.
 18. The method of claim 9,wherein the neurotoxic damage prevented is damage that is associatedwith inactivity, lethargy, and malaise.
 19. The method of claim 9,wherein the neurotoxic damage prevented is damage that is associatedwith chemotherapy and/or radiotherapy-induced depression, anxiety,melancholy, post-traumatic stress disorder or other mentalhealth/psychological disorder.
 20. The method of claims 9 and 16-19,wherein the agent is administered before, at the same time as, or afterthe injury.
 21. The method of claims 10-15, wherein the chemotherapyand/or radiotherapy agent is selected from a group consisting ofcisplatin, carboplatin, oxaliplatin, cyclophosphamide, altretamine,plicamydin, chlorambucil, chlormethine, ifosfamide, melphalan,carmustine, fotemustine, lomustine, streptozocin, busulfan, dacarbazine,mechlorethamine, procarbazine, temozolomide, thioTEPA, uramustine,paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinorelbine,hexamethylmelamine, etoposide, teniposide, methotrexate, pemetrexed,raltitrexed, cladribine, clofarabine, fludarabine, mercaptopurine,tioguanine, capecitabine, cytarabine, fluorouracil, fluxuridine,gemcitabine, daunorubicin, doxorubicin, epirubicin, idarubicin,mitoxantrone, valrubicin, bleomycin, hydroxyurea, mitomycin, topotecan,irinotecan, aminolevulinic acid, methyl aminolevulinate, porfimersodium, verteporfin, alitretinoin, altretamine, amsacrine, anagrelide,arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib,denileukin, diftitox, erlotinib, estramustine, gefitinib,hydroxycarbamide, imatinib, pentostatin, masoprocol, mitotane,pegaspargase, tretinoin, and/or α, β and γ-irradiation through directirradiation or administration of radiation emitting isotopes, orcombinations thereof.
 22. The method of any of claims 1-20, wherein theagent that increases the level of NAD⁺ is an NAD⁺ precursor.
 23. Themethod of claim 22, wherein the NAD⁺ precursor is selected from thegroup consisting of nicotinamide mononucleotide (NMN), nicotinic acid,nicotinamide, nicotinamide riboside (NR), nicotinic acid mononucleotide,nicotinic acid riboside, AICAR, adenosine, adenine, adenosinemonophosphate, an analog, hetero- or homo-dimers, oligomer or polymer ofany of the foregoing, or a salt or prodrug thereof.
 24. The method ofany one of claims 1-20, wherein the agent that increases the level ofNAD⁺ is an inhibitor of an NAD⁺ consuming enzyme such as CD38 or PARP.25. The method of any of claims 1-20, wherein the agent that increasesthe level of NAD⁺ is selected from the group consisting of an enzymeinvolved in NAD⁺ biosynthesis, an enzymatically active fragment of suchan enzyme, a nucleic acid encoding for an enzyme involved in NAD⁺biosynthesis, and an enzymatically active fragment of such a nucleicacid.
 26. The method of claim 25, wherein the enzyme is NMNAT-1, NMNAT2,NMNAT3 or NAMPT.
 27. The method of any of claims 1-10, wherein the agentthat increases the level of NAD⁺ is an activator to an enzyme involvedin NAD⁺ biosynthesis.
 28. The method of any one of claims 1-27, whereinthe agent that increases the level of NAD⁺ is administered at a dose ofbetween 0.5-5 grams per day.
 29. The method of any one of claims 1-17,wherein the subject is a human.
 30. An agent that increases the level ofNAD⁺ for use in preventing neurotoxic injury.
 31. An agent thatincreases the level of NAD⁺ for use in preventing neurocognitive andneuropathic decline.
 32. An agent that increases the level of NAD⁺ foruse in preventing or treating pain, neuropathies and associateddisorders; and providing increased resistance to pain, neuropathies andassociated disorders.
 33. An agent that increases the level of NAD⁺ foruse in increasing cognitive performance.
 34. An agent that increases thelevel of NAD⁺ for use in increasing voluntary activity, endurance,stamina.
 35. An agent that increases the level of NAD⁺ for use inpreventing cramps, tremors, spasms, paralysis, neuromuscular paralysis,hearing loss, vision impairment, taste loss, improving or preventingdecline in skills, gait, and co-ordination.
 36. An agent that increasesthe level of NAD⁺ for use in preventing or treating sexual dysfunctionassociated with nerve damage or impairment.
 37. An agent that increasesthe level of NAD⁺ for use in improving neuronal function and motorskills.
 38. An agent that increases the level of NAD⁺ for use inpreventing chemotherapy- and/or radiotherapy induced neurotoxic damagein a subject.
 39. The agent of claim 38, wherein the chemotherapy and/orradiotherapy-induced neurotoxic damage prevented is damage that isassociated with chemotherapy and/or radiotherapy-induced cognitiveimpairments (CICI).
 40. The agent of claim 38, wherein the chemotherapyand/or radiotherapy-induced neurotoxic damage prevented is damage thatis associated with chemotherapy and/or radiotherapy-induced peripheralneuropathies (CIPN).
 41. The agent of claim 38, wherein the chemotherapyand/or radiotherapy induced neurotoxic damage prevented is damage thatis associated with chemotherapy and/or radiotherapy-induced inactivity,lethargy or malaise.
 42. The agent of claim 38, wherein the chemotherapyand/or radiotherapy induced neurotoxic damage prevented is damage thatis associated with chemotherapy and/or radiotherapy-induced depression,anxiety, impaired sleep, circadian rhythm disorder, or otherpsychological disorder.
 43. The agent of any of claims 28-42, whereinthe agent is an NAD⁺ precursor.
 44. The agent of claim 43, wherein theNAD⁺ precursor is selected from the group consisting of nicotinamidemononucleotide (NMN), nicotinic acid, nicotinamide, nicotinamideriboside (NR), nicotinic acid mononucleotide, nicotinic acid riboside,AICAR, adenosine, adenine, adenosine monophosphate, an analog, hetero-or homo-dimer, oligomer or polymer of any of the foregoing, or a salt orprodrug thereof.
 45. The agent of any of claims 28-42, wherein the agentthat raises NAD+ is an inhibitor of an NAD+ consuming enzyme, such asCD38 or a PARP enzyme.
 46. The agent of any of claims 28-42, wherein theagent is selected from the group consisting of an enzyme involved inNAD⁺ biosynthesis, an enzymatically active fragment of such an enzyme, anucleic acid encoding for an enzyme involved in NAD⁺ biosynthesis, andan enzymatically active fragment of such a nucleic acid.
 47. The agentof claim 46, wherein the enzyme is NMNAT-1, NMNAT2, NMNAT3 or NAMPT. 48.The agent of any of claims 28-42, wherein the agent that increases thelevel of NAD⁺ is an activator to an enzyme involved in NAD⁺biosynthesis.
 49. An agent that increases the level of NAD⁺ for use inmanufacturing a medicament for preventing neural damage or decline. 50.An agent that increases the level of NAD⁺ for use in manufacturing amedicament for improving neural function, including improvedneurocognitive function.
 51. An agent that increases the level of NAD⁺for use in manufacturing a medicament for preventing chemotherapy and/orradiotherapy-induced neurotoxic damage in a subject.
 52. The agent ofclaim 51, wherein the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is damage that is associated withchemotherapy and/or radiotherapy-induced cognitive impairments (CICI).53. The agent of claim 38, wherein the chemotherapy and/orradiotherapy-induced neurotoxic damage prevented is damage that isassociated with chemotherapy and/or radiotherapy-induced peripheralneuropathies (CIPN).
 54. The composition of any of claims 49-51, whereinthe agent that increases the level of NAD⁺ is an NAD⁺ precursor.
 55. Theagent of claim 54, wherein the NAD⁺ precursor is selected from the groupconsisting of nicotinamide mononucleotide (NMN), nicotinic acid,nicotinamide, nicotinamide riboside (NR), nicotinic acid mononucleotide,nicotinic acid riboside, AICAR, adenosine, adenine, adenosinemonophosphate, an analog, hetero- or homo-dimer, oligomer or polymer ofany of the foregoing, or a salt or prodrug thereof.
 56. The agent of anyof claims 49-53, wherein the agent is selected from the group consistingof an enzyme involved in NAD⁺ biosynthesis, an enzymatically activefragment of such an enzyme, a nucleic acid encoding for an enzymeinvolved in NAD⁺ biosynthesis, and an enzymatically active fragment ofsuch a nucleic acid.
 57. The agent of claim 56, wherein the enzyme isNMNAT-1, NMNAT2, NMNAT3 or NAMPT.
 58. The agent of any of claims 49-53,wherein the agent is an activator to an enzyme involved in NAD⁺biosynthesis.
 59. A method for treating neurotoxic damage, neuropathy orimproving neural function in a subject, compromising administering to asubject in need thereof an effective amount of an agent that increasesthe level of NAD+ in the subject, whereby one of the symptoms ofneurotoxic damage is decreased.
 60. The method of claim 59, wherein theneurotoxic damage treated is damage that is associated with cognitiveimpairment.
 61. The method of claim 59, wherein the neurotoxic damagetreated is damage that is associated with peripheral neuropathy and/orpain.
 62. The method of claim 59, wherein the neurotoxic damage treatedis damage that is associated with inactivity, lethargy and malaise. 63.The method of claim 59, wherein the neurotoxic damage treated is damagethat is associated with depression, anxiety, post-traumatic stressdisorder, impaired sleep, circadian rhythm disruption, and otherneuropsychological disorders.
 64. A method for treating chemotherapyand/or radiotherapy-induced neurotoxic damage in a subject, comprisingadministering to a subject in need thereof an effective amount of anagent that increases the level of NAD⁺ in the subject, whereby one ormore symptoms of chemotherapy and/or radiotherapy-induced neurotoxicdamage is decreased.
 65. The method of claim 64, wherein thechemotherapy and/or radiotherapy-induced neurotoxic damage treated isdamage that is associated with chemotherapy and/or radiotherapy-inducedcognitive impairments (CICI).
 66. The method of claim 64, wherein thechemotherapy and/or radiotherapy-induced neurotoxic damage treated isdamage that is associated with chemotherapy-induced peripheralneuropathies (CIPN).
 67. The method of any of claims 64-66, wherein theone or more symptoms of chemotherapy and/or radiotherapy-inducedneurotoxic damage is selected from the group consisting of a burningsensation, a tingling sensation, loss of feeling, difficulty usingfingers to pick up or hold objects, dropping objects, difficulties withbalance, tripping or stumbling while walking, pressure or temperaturesensitivity, and sexual dysfunction.
 68. The method of claim 64, whereinthe chemotherapy and/or radiotherapy induced neurotoxic treated isdamage that is associated with inactivity, lethargy and malaise.
 69. Themethod of claim 64, wherein the chemotherapy and/or radiotherapy inducedneurotoxic treated is damage that is associated with depression,anxiety, impaired sleep, circadian rhythm disturbance, and other mentalhealth or neuropsychological disorders.
 70. The method of any of claims59-69, wherein the agent that increases the level of NAD⁺ is an NAD⁺precursor.
 71. The method of claim 70, wherein the NAD⁺ precursor isselected from the group consisting of nicotinamide mononucleotide (NMN),nicotinic acid, nicotinamide, nicotinamide riboside (NR), nicotinic acidmononucleotide, nicotinic acid riboside, AICAR, adenosine, adenine,adenosine monophosphate, an analog, hetero- or homo-dimer, oligomer orpolymer of any of the foregoing, or a salt or prodrug thereof.
 72. Themethod of any one of claims 59-69, wherein the agent that increases thelevel of NAD⁺ is administered at a dose of between 0.5-5 grams per day.73. The method of any of claims 59-72, wherein the agent that increasesthe level of NAD⁺ is selected from the group consisting of an enzymeinvolved in NAD⁺ biosynthesis, an enzymatically active fragment of suchan enzyme, a nucleic acid encoding for an enzyme involved in NAD⁺biosynthesis, and an enzymatically active fragment of such a nucleicacid.
 74. The method of claim 73, wherein the enzyme is NMNAT-1, NMNAT,NMNAT3 or NAMPT.
 75. The method of any of claims 59-72, wherein theagent that increases the level of NAD⁺ is an activator to an enzymeinvolved in NAD⁺ biosynthesis.
 76. The method of any one of claims59-75, wherein the subject is a human.
 77. The method of any one ofclaims 59-75, wherein the subject is an animal, such as a racehorse,companion pet or livestock.
 78. An agent that increases the level ofNAD⁺ for use in treating neural damage in a subject.
 79. An agent thatincreases the level of NAD⁺ for use in preventing, treating pain and/orincreasing resistance to pain.
 80. An agent that increases the level ofNAD⁺ for use in improving neural function in a subject, to enhancecognitive performance, motor skills, voluntary activity, stamina andendurance, and provide resistance to pain and neuropathy.
 81. The agentof claim 78, wherein the neural damage treated or prevented is damagethat is associated with cognitive impairment.
 82. The agent of claim 78,wherein the neural damage treated or prevented is damage that isassociated with peripheral neuropathy and/or pain.
 83. The agent ofclaim 78, wherein the neural damage treated or prevented is damage thatis associated with inactivity, lethargy and malaise.
 84. The agent ofclaim 78, wherein the neural damage treated or prevented is damage thatis associated with depression, anxiety, impaired sleep, circadian rhythmdisturbances, impaired mental health, and other neuropsychologicaldisorders.
 85. The agent of claim 78, wherein the neural damage treatedor prevented is damage that is associated with psychological oremotional stress and associated disorders, such as post-traumatic stressdisorder.
 86. An agent that increases the level of NAD⁺ for use intreating chemotherapy and/or radiotherapy-induced neurotoxic damage in asubject.
 87. The agent of claim 86, wherein the chemotherapy and/orradiotherapy-induced neurotoxic damage treated is damage that isassociated with chemotherapy and/or radiotherapy-induced cognitiveimpairments (CICI).
 88. The agent of claim 86, wherein the chemotherapyand/or radiotherapy-induced neurotoxic damage prevented is damage thatis associated with chemotherapy and/or radiotherapy-induced peripheralneuropathies (CIPN).
 89. The agent of claim 86, wherein the chemotherapyand/or radiotherapy-induced neurotoxic damage prevented is inactivity,lethargy and malaise.
 90. The agent of claim 86, wherein thechemotherapy and/or radiotherapy induced neurotoxic damage prevented isdepression, anxiety, impaired sleep, impaired circadian rhythm, mentalhealth disorders and other neuropsychological disorders.
 91. The agentof any of claims 78-90, wherein the agent is an NAD⁺ precursor.
 92. Theagent of claim 91, wherein the NAD⁺ precursor is selected from the groupconsisting of nicotinamide mononucleotide (NMN), nicotinic acid,nicotinamide, nicotinamide riboside (NR), nicotinic acid mononucleotide,nicotinic acid riboside, AICAR, adenosine, adenine, adenosinemonophosphate, an analog, hetero- or homo-dimer, oligomer or polymer ofany of the foregoing, or a salt or prodrug thereof.
 93. The agent of anyof claims 78-91, wherein the agent is selected from the group consistingof an enzyme involved in NAD⁺ biosynthesis, an enzymatically activefragment of such an enzyme, a nucleic acid encoding for an enzymeinvolved in NAD⁺ biosynthesis, and an enzymatically active fragment ofsuch a nucleic acid.
 94. The agent of claim 93, wherein the enzyme isNMNAT-1, NMNAT, NMNAT3 or NAMPT.
 95. The agent of any of claims 78-91,wherein the agent is an activator to an enzyme involved in NAD⁺biosynthesis.
 96. An agent that increases the level of NAD⁺ for use inmanufacturing a medicament for treating chemotherapy and/orradiotherapy-induced neurotoxic damage in a subject.
 97. The agent ofclaim 96, wherein the chemotherapy and/or radiotherapy-inducedneurotoxic damage treated is damage that is associated with chemotherapyand/or radiotherapy-induced cognitive impairments (CICI).
 98. The agentof claim 96, wherein the chemotherapy and/or radiotherapy-inducedneurotoxic damage prevented is damage that is associated withchemotherapy and/or radiotherapy-induced peripheral neuropathies (CIPN).99. An agent that increases NAD⁺ for improving pain tolerance.
 100. Anagent that increases NAD⁺ for treating phantom limbs.
 101. An agent thatincreases NAD⁺ delivered prior to, at the same time as, in combinationwith, after treatment with, or in place of pain therapies such asibuprofen, aspirin, paracetamol, opioids, and other pain therapies, forthe treatment of pain.
 102. An agent that increases NAD⁺ delivered priorto, at the same time as, in combination with, after treatment with, orin place of anti-inflammatory therapies, including corticosteroidsselected from the group consisting of dexamethasone andmethylprednisolone and non-steroidal anti-inflammatory agents selectedfrom the group consisting of ibuprofen, aspirin, indomethacin, COX-2inhibitors, and mefenamic acid for the treatment of pain andneuropathies.
 103. An agent that increases NAD⁺ for increasing voluntaryphysical activity, stamina and endurance.
 104. An agent that increasesNAD⁺ for improving cognitive performance.
 105. An agent that increasesNAD⁺ for treating or protecting against depression, anxiety,post-traumatic stress disorder, substance abuse, and other mental healthor neuropsychological disorders.
 106. An agent that increases NAD⁺ forpreventing or treating diabetic neuropathy.
 107. An agent that increasesNAD⁺ for preventing or treating substance abuse and addiction.
 108. Anagent that increases NAD⁺ for preventing neurocognitive orneurodevelopmental disorders caused by exposure to pollution includingair pollution, water pollution, and food contamination.
 109. An agentthat prevents or treats nerve and neuron damage.
 110. The agent of anyof claims 78-91 and 99-109, wherein the agent is an NAD⁺ precursor. 111.The agent of claim 110, wherein the NAD⁺ precursor is selected from thegroup consisting of nicotinamide mononucleotide (NMN), nicotinic acid,nicotinamide, nicotinamide riboside (NR), nicotinic acid mononucleotide,nicotinic acid riboside, AICAR, adenosine, adenine, adenosinemonophosphate, an analog, hetero- or homo-dimer, oligomer or polymer ofany of the foregoing, or a salt or prodrug thereof.
 112. The agent ofany of claims 78-91 and 99-109, wherein the agent is selected from thegroup consisting of an enzyme involved in NAD⁺ biosynthesis, anenzymatically active fragment of such an enzyme, a nucleic acid encodingfor an enzyme involved in NAD⁺ biosynthesis, and an enzymatically activefragment of such a nucleic acid.
 113. The agent of claim 112, whereinthe enzyme is NMNAT-1, NMNAT2, NMNAT3 or NAMPT.
 114. The agent of any ofclaims 78-91 and 99-109, wherein the agent is an activator to an enzymeinvolved in NAD⁺ biosynthesis.